中医药基于肺巨噬细胞极化调控重症肺炎的机制

ETHNOPHARMACOLOGICAL RELEVANCE Reyanning (RYN) mixture is a traditional Chinese medicine composed of Taraxacum, Polygonum cuspidatum, Scutellariae Barbatae and Patrinia villosa and is used for the treatment of acute respiratory system diseases with significant clinical efficacy. AIM OF THE STUDY Acute lung injury (ALI) is a common clinical disease characterized by acute respiratory failure. This study was conducted to evaluate the therapeutic effects of RYN on ALI and to explore its mechanism of action. MATERIALS AND METHODS Ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the chemical components of RYN. 7.5 mg/kg LPS was administered to induce ALI in rats. RYN was administered by gavage at doses of 2 ml/kg, 4 ml/kg or 8 ml/kg every 8 h for a total of 6 doses. Observations included lung histomorphology, lung wet/dry (W/D) weight ratio, lung permeability index (LPI), HE staining, Wright-Giemsa staining. ELISA was performed to detect the levels of TNF-α, IL-6, IL-10, Arg-1,UDPG. Immunohistochemical staining detected IL-6, F4/80 expression. ROS, MDA, SOD, GSH/GSSG were detected in liver tissues. Multiple omics techniques were used to predict the potential mechanism of action of RYN, which was verified by in vivo closure experiments. Immunofluorescence staining detected the co-expression of CD86 and CD206, CD86 and P2Y14, CD86 and UGP2 in liver tissues. qRT-PCR detected the mRNA levels of UGP2, P2Y14 and STAT1, and immunoblotting detected the protein expression of UGP2, P2Y14, STAT1, p-STAT1. RESULTS RYN was detected to contain 1366 metabolites, some of the metabolites with high levels have anti-inflammatory, antibacterial, antiviral and antioxidant properties. RYN (2, 4, and 8 ml/kg) exerted dose-dependent therapeutic effects on the ALI rats, by reducing inflammatory cell infiltration and oxidative stress damage, inhibiting CD86 expression, decreasing TNF-α and IL-6 levels, and increasing IL-10 and Arg-1 levels. Transcriptomics and proteomics showed that glucose metabolism provided the pathway for the anti-ALI properties of RYN and that RYN inhibited lung glycogen production and distribution. Immunofluorescence co-staining showed that RYN inhibited CD86 and UGP2 expressions. In vivo blocking experiments revealed that blocking glycogen synthesis reduced UDPG content, inhibited P2Y14 and CD86 expressions, decreased P2Y14 and STAT1 mRNA and protein expressions, reduced STAT1 protein phosphorylation expression, and had the same therapeutic effect as RYN. CONCLUSION RYN inhibits M1 macrophage polarization to alleviate ALI. Blocking glycogen synthesis and inhibiting the UDPG/P2Y14/STAT1 signaling pathway may be its molecular mechanism.

Acute lung injury (ALI) is a life-threatening syndrome characterized by dysregulated inflammatory responses, disruption of the alveolar–vascular barrier, and severe respiratory dysfunction. With a complex pathogenesis and high mortality, ALI remains a major clinical challenge. Traditional Chinese medicine (TCM) offers distinctive therapeutic advantages in ALI management through its integrated regulatory mechanism involving “multiple-components, multiple-targets, and multiple-pathways”. TCM monomers, TCM compound prescriptions, and Chinese proprietary medicines have been shown to attenuate pulmonary pathology by suppressing the release of pro-inflammatory mediator, inhibiting inflammatory signaling cascades, modulating immune cell polarization, and alleviating oxidative stress. Retrieve relevant literature from PubMed, Web of Science, and Google Scholar databases based on abstracts, conclusions, and experimental content. Based on the aforementioned literature, this review systematically examines the mechanistic basis by which TCM regulates inflammation in ALI, beginning with the pivotal role of inflammation in disease progression, and aims to provide insights to guide TCM pharmacological research and novel drug development in this field.

COVID-19 has posed unprecedented challenges to global public health since its outbreak. The Qing-Fei-Pai-Du decoction (QFPDD), a Chinese herbal formula, is widely used in China to treat COVID-19. It exerts an impressive therapeutic effect by inhibiting the progression from mild to critical disease in the clinic. However, the underlying mechanisms remain obscure. Both SARS-CoV-2 and influenza viruses elicit similar pathological processes. Their severe manifestations, such as acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), and viral sepsis, are correlated with the cytokine storm. During flu infection, QFPDD reduced the lung indexes and downregulated the expressions of MCP-1, TNF-[Formula: see text], IL-6, and IL-1[Formula: see text] in broncho-alveolar lavage fluid (BALF), lungs, or serum samples. The infiltration of neutrophils and inflammatory monocytes in lungs was decreased dramatically, and lung injury was ameliorated in QFPDD-treated flu mice. In addition, QFPDD also inhibited the polarization of M1 macrophages and downregulated the expressions of IL-6, TNF-[Formula: see text], MIP-2, MCP-1, and IP-10, while also upregulating the IL-10 expression. The phosphorylated TAK1, IKK[Formula: see text]/[Formula: see text], and I[Formula: see text]B[Formula: see text] and the subsequent translocation of phosphorylated p65 into the nuclei were decreased by QFPDD. These findings indicated that QFPDD reduces the intensity of the cytokine storm by inhibiting the NF-[Formula: see text]B signaling pathway during severe viral infections, thereby providing theoretical and experimental support for its clinical application in respiratory viral infections.

Acute respiratory distress syndrome (ARDS) is a critical pulmonary disorder triggered by multiple factors, with pathological mechanisms involving inflammatory storms, oxidative stress, alveolar-endothelial barrier disruption, and multiple cell death modalities (eg, pyroptosis and ferroptosis). Chinese herbal medicines(CHMs) and their active components have demonstrated their unique potential in the intervention of ARDS through multiple targets and multiple pathways approaches: (1) inhibiting the Wnt/β-catenin signaling pathway to mitigate inflammation; (2) regulating macrophage M1/M2 polarization; (3) activating the Sirtuin-3 (SIRT3) pathway to alleviate oxidative damage; (4) suppressing NLRP3 inflammasome-mediated pyroptosis; (5) improving barrier function via inhibition of the PI3K/AKT signaling pathway;(6) inhibiting ferroptosis through modulation of the Nrf2/SLC7A11/GPX4 axis. In the future, we can start from the pathogenesis of ARDS, and based on the efficacy and results of traditional Chinese medicine and its active components in regulating related signaling pathways to intervene in ARDS, provide references for the research and development of new drugs and clinical applications.

Sepsis is a life-threatening multiple organ dysfunction syndrome caused by the imbalance of the immune response to infection, featuring complex and variable conditions, and is one of the leading causes of mortality in ICU patients. Lung injury is a common organ damage observed in sepsis patients. Macrophages and Th17 cells, as crucial components of innate and adaptive immunity, play pivotal roles in the development of sepsis-induced acute lung injury (ALI). This review summarizes the alterations and mechanisms of macrophages and Th17 cells in sepsis-induced ALI. By focusing on the “cross-talk” between macrophages and Th17 cells, this review aims to provide a solid theoretical foundation for further exploring the therapeutic targets of traditional Chinese medicine formulas in the treatment of sepsis complicated with ALI, thereby offering insights and guidance for the clinical application of traditional Chinese medicine in managing sepsis-associated ALI.

Acute lung injury (ALI) is a common, severe respiratory disorder frequently related to acute lung inflammation. As crucial immunoregulatory cells, macrophages critically influence the pathological trajectory of ALI, with their functional states serving as predictive biomarkers for both lesion severity and patient recovery trajectories. Cepharanthine (CEP), a natural bisbenzylisoquinoline (BBIQ) alkaloid, was shown to have substantial anti-inflammatory properties. However, whether CEP can alleviate ALI by regulating macrophage polarization needs to be clarified. Therefore, the therapeutic effect of CEP in ALI was explored via H&E staining, enzyme-linked immunosorbent assays (ELISAs), immunofluorescence, and western blot. In vivo, experimental data demonstrated that CEP intervention significantly ameliorated mouse pathological alterations. Specifically, the secretion levels of pro-inflammatory cytokines IL-6 and TNF-α were dose-dependently downregulated, while the expression of the anti-inflammatory mediator IL-10 exhibited a significant upregulation trend. Immunofluorescence staining revealed that CEP suppressed lipopolysaccharide (LPS)-induced M1 macrophage polarization and increased M2 macrophage polarization. Moreover, western blot results showed that CEP inhibited TLR4/MAPK signaling pathway activation but increased AMPK phosphorylation and Nrf2/HO-1 expression. Experimental findings from in vitro studies aligned with observations corresponding to in vivo models. In summary, CEP can regulate macrophage polarization to protect against LPS-induced ALI by interfering with TLR4/MAPK signaling and activating the AMPK/Nrf2 pathway.

Dysregulated macrophage polarization is a critical pathological driver of sepsis-induced acute lung injury (ALI). However, the absence of novel therapeutic targets constitutes a significant translational barrier, underscoring the urgent need for advancements in precision medicine. In this study, we demonstrate that the natural product luteolin (LU) effectively promotes LPS-induced M1-to-M2 macrophage polarization by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Subsequently, thermal proteome profiling identifies receptor-type protein tyrosine phosphatase α (RPTPα) as a direct cellular target of LU in macrophages, which is validated by drug affinity responsive target stability, microscale thermophoresis, and surface plasmon resonance assays. Meanwhile, LU treatment inhibits RPTPα phosphatase activity. Molecular docking suggests that LU interacts with the 405PFTP408 motif, impairing substrate recognition and subsequently suppressing the enzymatic activity of RPTPα. Furthermore, transcriptomic profiling reveals that LU significantly dysregulates 1,402 genes. Integrated kyoto encyclopedia of genes and genomes (KEGG) and gene set enrichment analysis demonstrate that LU suppresses the tumor necrosis factor (TNF) signaling pathways, which is reversed upon RPTPα silencing. In vivo, LU exhibits potent anti-inflammatory effects in both BALB/c mice with sepsis-induced ALI and CuSO4-induced zebrafish inflammation models. Collectively, our study reveals that RPTPα is a potential therapeutic target for modulating macrophage polarization. Moreover, LU may serve as a lead compound targeting RPTPα for the treatment of sepsis-induced ALI.

Background: Sepsis, a severe infectious systemic syndrome with high morbidity and mortality, is pathologically characterized by multi-organ dysfunction, with pulmonary involvement predominating as acute lung injury (ALI) or its severe progression to acute respiratory distress syndrome. Contemporary therapeutic strategies exhibit limited efficacy, while traditional Chinese medicine (TCM) grounded in millennia of clinical empiricism demonstrates unique pharmacological advantages through multi-component and multi-target regulation. Summary: The mechanism underlying sepsis-induced ALI centers on dysregulated inflammatory response, redox imbalance, and coagulopathy. This review systematically evaluates the effectiveness, mechanism, and clinical research progress of eight TCM formulas in the treatment of sepsis and ALI. Accumulating fundamental research and clinical trials demonstrate the potential of these TCM formulas in treating sepsis-induced ALI. The challenges and opportunities of TCM formulas in treating, including but not limited to, sepsis-induced ALI were emphasized. Key Message: This review bridges traditional therapeutic wisdom with modern pathogenesis understanding, offering novel combinatorial strategies for sepsis-induced ALI management.

… Pulmonary infections are a significant concern for HIV/AIDS patients, and the role of macrophage polarization is … QFPY reduces lung infections by regulating macrophage polarization. …

ETHNOPHARMACOLOGICAL RELEVANCE Sepsis is a fatal disease induced by an abnormal anti-infection immune response. Macrophage M1/M2 polarization responses are essential for the systemic inflammatory response process in sepsis. Taohong Siwu Decoction (THSWD) is a traditional Chinese medicine (TCM) prescription that has been confirmed to regulate the macrophage M1/M2 polarization to improve inflammatory damage. However, the active components and the mechanisms by which it alleviates inflammatory injury in sepsis remain unclear. Amygdalin (AMY) is an active component found in Persicae Semen. Great attention has been paid to AMY, which is used in pharmacotherapy to manage inflammatory disorders. Further investigation is warranted to determine how AMY, as one of the active components of THSWD, contributes to its anti-sepsis effects and to clarify the underlying mechanism of action. AIM OF THE STUDY This work evaluated the protection of THSWD and AMY, one of its representative active components, against sepsis-related inflammatory injury and the mechanisms involved. MATERIALS AND METHODS Using the cecal ligation and puncture (CLP) procedure, this study constructed a sepsis mouse model. Subsequently, histopathology, echocardiography, TUNEL staining and ELISA were conducted to assess the protection of THSWD against inflammatory injury in CLP mice. Network pharmacology, molecular docking, molecular dynamics simulations, cellular thermal shift assay and SPRi were performed for verifying the mechanism of THSWD and its active component Amygdalin (AMY) in improving inflammatory injury in sepsis. Moreover, the protection of AMY against inflammatory injury, as well as its role in regulating M1 macrophage polarization through the RAGE pathway, was investigated using qRT-PCR, Western blotting, immunofluorescence staining, and immunohistochemical staining. In vitro, M1-type polarization was induced in RAW 264.7 cells and BMDMs using LPS stimulation, thereby verifying the effects of AMY. The RAGE inhibitor FPS-ZM1 was also used for further investigation in vitro and in vivo. RESULTS In vivo, THSWD significantly protected against inflammation-induced heart and lung tissue injuries in CLP mice. Bioinformatics analysis and other studies revealed that AMY, an active component of THSWD, might directly regulate RAGE to inhibit inflammatory response damage. AMY protected against inflammatory injury through inhibiting M1 macrophage polarization in sepsis by directly suppressing RAGE/NF-κB/MAPK pathways in vivo. According to our in vitro study results, AMY blocked RAGE activity to mitigate the LPS-mediated M1-type polarization in RAW 264.7 cells and BMDMs. Notably, AMY's protection in vivo and in vitro was not markedly enhanced by combining FPS-ZM1, consistent with the pooled effect of AMY and FPS-ZM1 on a RAGE-related pathway under our experimental conditions. CONCLUSIONS THSWD and AMY, one of its active components, inhibit M1 macrophage polarization and alleviate inflammatory injury in sepsis, at least partially by targeting RAGE and modulating the RAGE-mediated NF-κB/MAPK signaling pathway.

Acupuncture is used in the treatment of a variety of inflammatory conditions and diseases. However, the mechanisms of its anti-inflammatory action are complex and have not been systematically investigated. Macrophages are key components of the innate immune system, thus, balancing the M1/M2 macrophage ratio and modulating cytokine levels in the inflammatory environment may be desirable therapeutic goals. Evidence has shown that acupuncture has anti-inflammatory actions that affect multiple body systems, including the immune, locomotory, endocrine, nervous, digestive, and respiratory systems, by downregulating pro-inflammatory M1 and upregulating anti-inflammatory M2 macrophages, as well as by modulating associated cytokine secretion. Macrophage polarization is controlled by the interlocking pathways of extrinsic factors, the local tissue microenvironment, and the neural-endocrine-immune systems. It has been suggested that polarization of T lymphocytes and cytokine secretions resulting in modulation of the autonomic nervous system and the hypothalamic–pituitary–adrenal axis, may be upstream mechanisms of acupuncture-induced macrophage polarization. We further propose that macrophage polarization could be the principal pathway involved in acupuncture immune regulation and provide the scientific basis for the clinical application of acupuncture in inflammatory conditions.

BACKGROUND Acute lung injury (ALI) is a continuum of lung changes caused by multiple lung injuries, characterized by a syndrome of uncontrolled systemic inflammation that often leads to significant morbidity and death. Anti-inflammatory is one of its treatment methods, but there is no safe and available drug therapy. Syringic acid (SA) is a natural organic compound commonly found in a variety of plants, especially in certain woody plants and fruits. In modern pharmacological studies, SA has anti-inflammatory effects and therefore may be a potentially safe and available compound for the treatment of acute lung injury. PURPOSE This study attempts to reveal the protective mechanism of SA against ALI by affecting the polarization of macrophages and the activation of NF-κB signaling pathway. Trying to find a safer and more effective drug therapy for clinical use. METHODS We constructed the ALI model using C57BL/6 mice by intratracheal instillation of LPS (10 mg/kg). Histological analysis was performed with hematoxylin and eosin (H&E). The wet-dry ratio of the whole lung was measured to evaluate pulmonary edema. The effect of SA on macrophage M1-type was detected by flow cytometry. BCA protein quantification method was used to determine the total protein concentration in bronchoalveolar lavage fluid (BALF). The levels of Interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α in BALF were determined by the ELISA kits, and RT-qPCR was used to detect the expression levels of IL-6, IL-1β and TNF-α mRNA of lung tissue. Western blot was used to detect the expression levels of iNOS and COX-2 and the phosphorylation of p65 and IκBα in the NF-κB pathway in lung tissue. In vitro experiments were conducted with RAW267.4 cell inflammation model induced by 100 ng/ml LPS and A549 cell inflammation model induced by 10 μg/ml LPS. The effects of SA on M1-type and M2-type macrophages of RAW267.4 macrophages induced by LPS were detected by flow cytometry. The toxicity of compound SA to A549 cells was detected by MTT method which to determine the safe dose of SA. The expressions of COX-2 and the phosphorylation of p65 and IκBα protein in NF-κB pathway were detected by Western blot. RESULTS We found that the pre-treatment of SA significantly reduced the degree of lung injury, and the infiltration of neutrophils in the lung interstitium and alveolar space of the lung. The formation of transparent membrane in lung tissue and thickening of alveolar septum were significantly reduced compared with the model group, and the wet-dry ratio of the lung was also reduced. ELISA and RT-qPCR results showed that SA could significantly inhibit the production of IL-6, IL-1β, TNF-α. At the same time, SA could significantly inhibit the expression of iNOS and COX-2 proteins, and could inhibit the phosphorylation of p65 and IκBα proteins. in a dose-dependent manner. In vitro experiments, we found that flow cytometry showed that SA could significantly inhibit the polarization of macrophages from M0 type macrophages to M1-type macrophages, while SA could promote the polarization of M1-type macrophages to M2-type macrophages. The results of MTT assay showed that SA had no obvious cytotoxicity to A549 cells when the concentration was not higher than 80 μM, while LPS could promote the proliferation of A549 cells. In the study of anti-inflammatory effect, SA can significantly inhibit the expression of COX-2 and the phosphorylation of p65 and IκBα proteins in LPS-induced A549 cells. CONCLUSION SA has possessed a crucial anti-ALI role in LPS-induced mice. The mechanism was elucidated, suggesting that the inhibition of macrophage polarization to M1-type and the promotion of macrophage polarization to M2-type, as well as the inhibition of NF-κB pathway by SA may be the reasons for its anti-ALI. This finding provides important molecular evidence for the further application of SA in the clinical treatment of ALI.

… The Chinese herbal medicine Aster exhibits a protective effect against … by which shionone modulates M1/M2 macrophage polarization to alleviate LPS-induced acute lung injury. …

Lung macrophages constitute the first line of defense against airborne particles and microbes and are key to maintaining pulmonary immune homeostasis. There is increasing evidence suggesting that macrophages also participate in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), including the modulation of inflammatory responses and the repair of damaged lung tissues. The diversity of their functions may be attributed to their polarized states. Classically activated or inflammatory (M1) macrophages and alternatively activated or anti-inflammatory (M2) macrophages are the two main polarized macrophage phenotypes. The precise regulatory mechanism of macrophage polarization is a complex process that is not completely understood. A growing body of literature on immunometabolism has demonstrated the essential role of immunometabolism and its metabolic intermediates in macrophage polarization. In this review, we summarize macrophage polarization phenotypes, the role of immunometabolism, and its metabolic intermediates in macrophage polarization and ALI/ARDS, which may represent a new target and therapeutic direction.

High heterogeneity of macrophage is associated with its functions in polarization to different functional phenotypes depending on environmental cues. Macrophages remain in balanced state in healthy subject and thus macrophage polarization may be crucial in determining the tissue fate. The two distinct populations, classically M1 and alternatively M2 activated, representing the opposing ends of the full activation spectrum, have been extensively studied for their associations with several disease progressions. Accumulating evidences have postulated that the redox signalling has implication in macrophage polarization and the key roles of M1 and M2 macrophages in tissue environment have provided the clue for the reasons of ROS abundance in certain phenotype. M1 macrophages majorly clearing the pathogens and ROS may be crucial for the regulation of M1 phenotype, whereas M2 macrophages resolve inflammation which favours oxidative metabolism. Therefore how ROS play its role in maintaining the homeostatic functions of macrophage and in particular macrophage polarization will be reviewed here. We also review the biology of macrophage polarization and the disturbance of M1/M2 balance in human diseases. The potential therapeutic opportunities targeting ROS will also be discussed, hoping to provide insights for development of target-specific delivery system or immunomodulatory antioxidant for the treatment of ROS-related diseases.

Background: Macrophage polarization toward the M2 phenotype may attenuate inflammation and have a therapeutic effect in acute lung injury (ALI). Objective: To investigate the role of electroacupuncture (EA) pretreatment on the inflammatory response and macrophage polarization in a septic rat model of lipopolysaccharide (LPS)-induced ALI. Methods: Male Sprague Dawley rats (n = 24) were randomly divided into three groups (n = 8 each): control (Ctrl), ALI (LPS) and pre-EA (LPS + EA pretreatment). ALI and pre-EA rats were injected with LPS via the caudal vein. Pulmonary edema was assessed by left upper pulmonary lobe wet-to-dry (W/D) ratios. Lung injury scores were obtained from paraffin-embedded and hematoxylin and eosin-stained sections of the left lower pulmonary lobe. Inflammatory activation was quantified using serum tumor necrosis factor (TNF)-α, interleukin (IL)-1β, transforming growth factor (TGF)-β and IL-10 levels measured by enzyme linked immunosorbent assay (ELISA). Macrophage phenotype was determined by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Results: Mean lung W/D ratio was significantly lower and serum IL-1β levels were decreased in pre-EA rats compared to ALI rats (P < 0.05). TNF-α mRNA expression was decreased and mannose receptor (MR) and Arg1 mRNA expression was increased in the lung tissues of pre-EA rats compared to ALI rats (P < 0.01). Arg1 protein expression was similarly increased in the lung tissues of pre-EA rats compared to ALI rats (P < 0.05). Conclusion: EA pretreatment may play a protective role by promoting macrophage polarization to the M2 phenotype in a septic rat model of LPS-induced ALI.

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a common respiratory disease characterized by hypoxemia and respiratory distress. It is associated with high morbidity and mortality. Due to the complex pathogenesis of ALI, the clinical management of patients with ALI/ARDS is challenging, resulting in numerous post-treatment sequelae and compromising the quality of life of patients. Macrophages, as a class of innate immune cells, play an important role in ALI/ARDS. In recent years, the functions and phenotypes of macrophages have been better understood due to the development of flow cytometry, immunofluorescence, single-cell sequencing and spatial genomics. However, no macrophage-targeted drugs for the treatment of ALI/ARDS currently exist in clinical practice. Natural products are important for drug development, and it has been shown that numerous natural compounds from herbal medicine can alleviate ALI/ARDS caused by various factors by modulating macrophage abnormalities. In the present review, the natural products from herbal medicine that can modulate macrophage abnormalities in ALI/ARDS to treat ALI/ARDS are introduced, and their mechanisms of action, discovered in the previous five years (2019–2024), are presented. This will provide novel ideas and directions for further research, to develop new drugs for the treatment of ALI/ARDS.

… mouse model of viral pneumonia, nanozyme aggregates into … macrophage polarization to the prohealing (M2) phenotype. … in a mouse viral pneumonia model with secondary bacterial …

Acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome, is a life-threatening disease closely associated with an imbalance of M1/M2 macrophage polarization. However, current therapeutic strategies for ALI are controversial due to their side effects, restricted administration routes, or poor targeted delivery. The development of herbal medicine has uncovered numerous anti-inflammatory compounds potentially beneficial for ALI therapy. One such compound is the bergapten, a coumarin, which has been isolated from Ficus simplicissima Lour. However, it's been used as an anti-cancer drug and it's effects on ALI remain unexplored. The poor solubility and biodistribution of bergapten heavily limit its application. In this timely report, we developed a bioactive and lung-targeting lipid-nanomedicine by integrating bergapten and DPPC liposome, named as Ber-lipo. A comprehensive series of in vitro experiments confirmed the anti-inflammatory effects of Ber-lipo and its protective roles in maintaining the homeostasis of macrophage polarization and epithelial–endothelial integrity. In a lipopolysaccharide (LPS)-induced ALI mouse model, Ber-lipo can target inflamed lungs and significantly improve lung edema, tissue injury, and pulmonary function, relieve body weight loss, pulmonary permeability, and proinflammatory status, and especially maintain a balance of M1/M2 macrophage polarization. Furthermore, RNA sequencing analysis showed Ber-lipo's potential in effectively treating inflammatory lung diseases such as pneumonia, inhibiting proinflammatory signals, and altering the transcriptome of M1/M2 macrophages-associated genes in lung tissues. Molecular docking and Western blot analyses validated that Ber-lipo suppressed the activation of the TLR4/MyD88/NF-κB signaling axis responsible for ALI progression. In conclusion, this study demonstrates for the first time that new inhalable nanomedicine (Ber-lipo) can target inflamed lungs and ameliorates ALI by reprogramming macrophage polarization to an anti-inflammatory state via inactivating the TLR4/MyD88/NF-κB pathway, hence providing a promising strategy for enhanced ALI therapy in the clinic.

Influenza is caused by a respiratory virus and has a major global impact on human health. Influenza A viruses in particular are highly pathogenic to humans and have caused multiple pandemics. An important consequence of infection is viral pneumonia, and with serious complications of excessive inflammation and tissue damage. Therefore, simultaneously reducing direct damage caused by virus infection and relieving indirect damage caused by excessive inflammation would be an effective treatment strategy. Lycium barbarum glycopeptide (LbGp) is a mixture of five highly branched polysaccharide-protein conjuncts (LbGp1-5) isolated from Lycium barbarum fruit. LbGp has pro-immune activity that is 1-2 orders of magnitude stronger than that of other plant polysaccharides. However, there are few reports on the immunomodulatory and antiviral activities of LbGp. In this study, we evaluated the antiviral and immunomodulatory effects of LbGp in vivo and in vitro and investigated its therapeutic effect on H1N1-induced viral pneumonia and mechanisms of action. In vitro, cytokine secretion, NF-κB p65 nuclear translocation, and CD86 mRNA expression in LPS-stimulated RAW264.7 cells were constrained by LbGp treatment. In A549 cells, LbGp can inhibit H1N1 infection by blocking virus attachment and entry action. In vivo experiments confirmed that administration of LbGp can effectively increase the survival rate, body weight and decrease the lung index of mice infected with H1N1. Compared to the model group, pulmonary histopathologic symptoms in lung sections of mice treated with LbGp were obviously alleviated. Further investigation revealed that the mechanism of LbGp in the treatment of H1N1-induced viral pneumonia includes reducing the viral load in lung, regulating the phenotype of pulmonary macrophages, and inhibiting excessive inflammation. In conclusion, LbGp exhibits potential curative effects against H1N1-induced viral pneumonia in mice, and these effects are associated with its good immuno-regulatory and antiviral activities.

Macrophages are pivotal innate immune cells that play essential roles in pathogen recognition, inflammation modulation, and tissue repair during pulmonary infections. Macrophages have remarkable plasticity that is shaped by diverse external stimuli to adapt to the dynamic lung microenvironment. Traditional models of macrophage polarization (M1/M2) cannot capture the full complexity of macrophage heterogeneity and diverse functions during lung infections. Recent advances in single‐cell omics have provided new insights into distinct macrophage subtypes, revealing their unique transcriptional profiles across various stages of infection. This review focuses on the functional plasticity of pulmonary macrophages and how environmental cues modulate their activation and effector functions. An integrative classification framework that defines six major functional macrophage subtypes in pulmonary infections, based on single‐cell omics with functional perspectives is proposed. This framework refines the understanding of macrophage heterogeneity and offers a foundation for developing targeted immunotherapeutic strategies against lung infections.

… This review describes pulmonary macrophage phenotypes … of community-acquired pneumonia and AMs have been … , however the associated macrophage phenotype is unclear. …

… pneumoniae infection we studied pneumococcal pneumonia … a feature of the alternative (M2) macrophage phenotype, and … that drive the phenotype switch from fibroblasts to …

… NO accumulation in macrophages initiates an apoptotic … , decreases pneumococcalassociated macrophage apoptosis. … NO accumulation switches the macrophage phenotype from an …

ABSTRACT The outcome of cryptococcal pneumonia correlates with local macrophage polarization status, as M1 and M2 polarization marks protective and nonprotective responses, respectively. Overall, pulmonary macrophage polarization status changes over time during a cryptococcal infection. This could have been caused by repolarization of individual macrophages or by a replacement of M2-polarized cells by new M1-polarized cells. To explore the ability of macrophages to change between polarization states, we conducted a series of experiments using in vitro macrophages. Coculture of macrophages with Cryptococcus neoformans resulted in development of a weak M1-like phenotype, with modestly increased inducible nitric oxide synthase (iNOS) but lacking interleukin 6 (IL-6) induction. The C. neoformans-induced M1-like polarization state was plastic, as macrophages stimulated first with C. neoformans and then with gamma interferon (IFN-γ) or IL-4 expressed mRNA polarization patterns similar to those stimulated with cytokines alone. To further evaluate macrophage polarization plasticity, cytokine stimulatory conditions were established which fully polarized macrophages. IFN-γ and IL-4 stimulation differentially induced complete M1 and M2 polarization, defined by differential expression of marker mRNA panels, surface marker expression, and tumor necrosis factor alpha (TNF-α) protein production. Switching IFN-γ- to IL-4-stimulating conditions, and vice versa, resulted in uniform changes in profiles of polarization marker genes consistent with the most recent cytokine environment. Furthermore, the ability of sequentially stimulated macrophages to inhibit C. neoformans reflected the most recent polarizing condition, independent of previous polarization. Collectively, these data indicate that M1/M2 macrophage polarization phenotypes are highly plastic to external signals, and interventions which therapeutically repolarize macrophages could be beneficial for treatment of cryptococcosis. IMPORTANCE Our studies reveal how a major opportunistic fungal pathogen, Cryptococcus neoformans, interacts with macrophages, immune cells which can ingest and kill invading pathogens. Macrophages play a crucial role in the pathogenesis of cryptococcal infection, as their polarization phenotype determines the outcome of the battle between the infected host and C. neoformans. This study suggests that dynamic changes in polarization of macrophages at the level of individual cells are an important characteristic of in vivo cryptococcosis, as they occur throughout the natural course of infection. We demonstrate that macrophages can rapidly and uniformly reverse their polarization phenotype in response to dynamic signaling conditions and lose or regain their fungicidal function. Demonstrating importance of these pathways may become a cornerstone for novel therapeutic strategies for treatment of cryptococcosis in both immunocompromised and immunocompetent patients. Our studies reveal how a major opportunistic fungal pathogen, Cryptococcus neoformans, interacts with macrophages, immune cells which can ingest and kill invading pathogens. Macrophages play a crucial role in the pathogenesis of cryptococcal infection, as their polarization phenotype determines the outcome of the battle between the infected host and C. neoformans. This study suggests that dynamic changes in polarization of macrophages at the level of individual cells are an important characteristic of in vivo cryptococcosis, as they occur throughout the natural course of infection. We demonstrate that macrophages can rapidly and uniformly reverse their polarization phenotype in response to dynamic signaling conditions and lose or regain their fungicidal function. Demonstrating importance of these pathways may become a cornerstone for novel therapeutic strategies for treatment of cryptococcosis in both immunocompromised and immunocompetent patients.

Community-acquired pneumonia is a widespread disease with significant morbidity and mortality. Alveolar macrophages are tissue-resident lung cells that play a crucial role in innate immunity against bacteria that cause pneumonia. We hypothesized that alveolar macrophages display adaptive characteristics after resolution of bacterial pneumonia. We studied mice one to six months after self-limiting lung infections with Streptococcus pneumoniae, the most common cause of bacterial pneumonia. Alveolar macrophages, but not other myeloid cells recovered from the lung, showed long-term modifications of their surface marker phenotype. The remodeling of alveolar macrophages was: (i) long-lasting (still observed 6 months post infection), (ii) regionally localized (only observed in the affected lobe after lobar pneumonia), and (iii) associated with macrophage-dependent enhanced protection against another pneumococcal serotype. Metabolomic and transcriptomic profiling revealed that alveolar macrophages of mice that recovered from pneumonia had new baseline activities and altered responses to infection that better resembled those of adult humans. The enhanced lung protection after mild and self-limiting bacterial respiratory infections includes a profound remodeling of the alveolar macrophage pool that is long-lasting, compartmentalized, and manifest across surface receptors, metabolites, and both resting and stimulated transcriptomes.

Summary From birth onward, the lungs are exposed to the external environment and therefore harbor a complex immunological milieu to protect this organ from damage and infection. We investigated the homeostatic role of the epithelium-derived alarmin interleukin-33 (IL-33) in newborn mice and discovered the immediate upregulation of IL-33 from the first day of life, closely followed by a wave of IL-13-producing type 2 innate lymphoid cells (ILC2s), which coincided with the appearance of alveolar macrophages (AMs) and their early polarization to an IL-13-dependent anti-inflammatory M2 phenotype. ILC2s contributed to lung quiescence in homeostasis by polarizing tissue resident AMs and induced an M2 phenotype in transplanted macrophage progenitors. ILC2s continued to maintain the M2 AM phenotype during adult life at the cost of a delayed response to Streptococcus pneumoniae infection in mice. These data highlight the homeostatic role of ILC2s in setting the activation threshold in the lung and underline their implications in anti-bacterial defenses.

Macrophages polarized to M1 (pro-inflammation) or M2 (anti-inflammation) phenotypes in response to environmental signals. In this study, we examined the polarization of alveolar macrophage (AM), following induction by different influenza virus strains (ST169 (H1N1), ST602 (H3N2) and HKG9 (H9N2)). Macrophages from other tissues or cell line exert alternative responding pattern, and AM is necessary for investigating the respiratory system. AM polarized toward the M1 phenotype after 4 hours of infection by all three virus strains, and AM to presented M2b phenotype after 8 hours induction, and immunosuppressive phenotype after 24 hours of induction. Protein expression assay showed similar results as the gene expression analysis for phenotype verification. The ELISA assay showed that TNF-α secretion was up-regulated after 4 and 8 hours of infection by influenza viruses, and it returned to basal levels after 24 hours of infection. IL-10 expression was elevated after 8 and 24 hours of infection. Immunofluorescence showed that iNOS expression was up-regulated but not Arg1 expression. Influenza virus notably increased phospho-Akt but not phospho-Erk1/2 or phospho-p38, and the AM polarization pattern have been changed by LY294002 (PI3K inhibitor). In conclusion, our results demonstrate the dynamic polarization of AM induced by influenza viruses, and suggested that PI3K/Akt signaling pathway modulates AM polarization to M1/M2b.

CD206, a mannose receptor, is mainly expressed on the surface of alternatively activated macrophages where it acts as a pattern recognition receptor and plays a role in innate and adaptive immunity. This study investigated serum soluble CD206 (sCD206) levels in community-acquired pneumonia (CAP) and examined their clinical significance. sCD206 concentrations were measured in the sera of two independent cohorts with CAP (127 and 125 patients, respectively) and 42 controls. The expression of CD206 in the lung from autopsied cases was also examined. Patients with CAP showed significantly elevated sCD206 levels than did the controls (p < 0.0001). Notably, fatal CAP patients had more than two-fold higher sCD206 concentrations than survivors in both cohorts (p < 0.0001). Serum sCD206 concentrations were associated with Pneumonia Severity Index (PSI) and CURB-65 values. Importantly, even fatal CAP patients classified as PSI I-IV, CURB65 0–2 or age <75 years had comparatively higher levels of sCD206 than those classified as PSI V, CURB-65 3–5 or age ≥75 years. Immunohistochemically, the infiltration of CD206+ macrophages was found in the lungs of fatal cases. Elevated levels of sCD206 are associated with CAP prognosis, suggesting sCD206 might be a potential biomarker to predict severity for CAP.

Acute lung injury (ALI) is a common clinical disease with high morbidity in both humans and animals. Ginsenoside Rg3, a type of traditional Chinese medicine extracted from ginseng, is widely used to cure many inflammation-related diseases. However, the specific molecular mechanism of the effects of ginsenoside Rg3 on inflammation has rarely been reported. Thus, we established a mouse model of lipopolysaccharide (LPS)-induced ALI to investigate the immune protective effects of ginsenoside Rg3 and explore its molecular mechanism. In wild type (WT) mice, we found that ginsenoside Rg3 treatment significantly mitigated pathological damages and reduced myeloperoxidase (MPO) activity as well as the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6); furthermore, the production of anti-inflammatory mediators interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), polarization of M2 macrophages and expression levels of the phosphorylation of phosphatidylinositol 3-hydroxy kinase (PI3K), protein kinase B (PKB, also known as AKT), mammalian target of rapamycin (mTOR) and Mer receptor tyrosine kinase (MerTK) were promoted. However, there were no significant differences with regards to the pathological damage, MPO levels, inflammatory cytokine levels, and protein expression levels of the phosphorylation of PI3K, AKT and mTOR between the LPS treatment group and ginsenoside Rg3 group in MerTK-/- mice. Taken together, the present study demonstrated that ginsenoside Rg3 could attenuate LPS-induced ALI by decreasing the levels of pro-inflammatory mediators and increasing the production of anti-inflammatory cytokines. These processes were mediated through MerTK-dependent activation of its downstream the PI3K/AKT/mTOR pathway. These findings identified a new site of the specific anti-inflammatory mechanism of ginsenoside Rg3.

BACKGROUND Quercetin has received extensive attention for its therapeutic potential treating respiratory syncytial virus (RSV) infection diseases. Recent studies have highlighted quercetin's ability of suppressing alveolar macrophages (AMs)-derived lung inflammation. However, the anti-inflammatory mechanism of quercetin against RSV infection still remains elusive. PURPOSE This study aims to elucidate the mechanism about quercetin anti-inflammatory effect on RSV infection. METHODS BALB/c mice were intranasally infected with RSV and received quercetin (30, 60, 120 mg/kg/d) orally for 3 days. Additionally, an in vitro infection model utilizing mouse alveolar macrophages (MH-S cells) was employed to validate the proposed mechanism. RESULTS Quercetin exhibited a downregulatory effect on glycolysis and tricarboxylic acid (TCA) cycle metabolism in RSV-infected AMs. However, it increased itaconic acid production, a metabolite derived from citrate through activating immune responsive gene 1 (IRG1), and further inhibiting succinate dehydrogenase (SDH) activity. While the suppression of SDH activity orchestrated a cascading downregulation of Hif-1α/NLRP3 signaling, ultimately causing AMs polarization from M1 to M2 phenotypes. CONCLUSION Our study demonstrated quercetin stimulated IRG1-mediated itaconic acid anabolism and further inhibited SDH/Hif-1α/NLRP3 signaling pathway, which led to M1 to M2 polarization of AMs so as to ameliorate RSV-induced lung inflammation.

Acute lung injury (ALI) is a severe pulmonary disorder characterized by inflammation, oxidative stress, and poor pulmonary barrier, resulting in high incidence and mortality. Due to no specific therapeutic agents, therapeutic strategies are urgently required. Ginkgo biloba, a living fossil in the plant kingdom, has been employed for millennia in treating lung diseases. Here, we isolated and characterized extracellular vesicles from G. biloba (GbEVs). GbEVs demonstrated excellent stability and specific tropism for the lungs. Proteomic analysis and nontarget metabolomics revealed a distinct profile enriched in peroxidases and containing small amounts of ginkgolides and flavonoids, implying potential antioxidant and anti-inflammatory properties. In vitro, GbEVs significantly suppressed lipopolysaccharide (LPS)-induced cytokine storm and reactive oxygen species (ROS) production, thereby mitigating inflammatory responses, preserving epithelial-endothelial integrity, and restoring the balance of macrophage subsets. In the ALI model, GbEV administration significantly restored weight loss, improved pulmonary edema, alleviated tissue damage, and relieved pro-inflammatory states, especially maintaining the balance of M1/M2 macrophage polarization. Furthermore, we stablished a plant cell suspension culture system to scale up the production of GbEV-like nanovesicles with comparable properties, in similar morphology and bioactivity. Our research has identified GbEVs as a pharmacological basis for G. biloba and, for the first time, demonstrated its potent efficacy against inflammatory diseases, particularly pneumonia.

BACKGROUND Macrophages play a pivotal role in the development and recovery of acute lung injury (ALI), wherein their phenotypic differentiation and metabolic programming are orchestrated by mitochondria. Specifically, the mitochondrial calcium uniporter (MCU) regulates mitochondrial Ca2+ (mCa2+) uptake and may bridge the metabolic reprogramming and functional regulation of immune cells. However, the precise mechanism on macrophages remains elusive. Shikonin, a natural naphthoquinone, has demonstrated efficacy in mitigating ALI and suppressing glycolysis in macrophages, yet which mechanism remains to be fully elucidated. PURPOSE This study explored whether Shikonin ameliorated ALI via modulating MCU-mediated mCa2+ and macrophage polarization. METHODS This study firstly examined the protective effects of Shikonin on LPS-induced ALI mice, and investigated whether it is depends on macrophage by depleting macrophage using clodronate liposomes. The regulatory effect of Shikonin on macrophage polarization and mitochondrial MCU/Ca2+ signal was testified on RAW264.7 cells, and further validated by knocking-down MCU expression or by using RU360, an MCU inhibitor. Additionally, the crucial role of MCU in the therapeutic effect of Shikonin, along with its regulation on macrophage polarization was validated in mice with LPS-induced ALI under the intervention of RU360. RESULTS Shikonin alleviated LPS-induced mice ALI, down-regulated inflammatory cytokines and inhibited the pro-inflammatory polarization of macrophages. Intravenous injection of clodronate liposomes on mice abolished the protective effects of Shikonin on ALI. On RAW264.7 cells, LPS&IFN decreased the protein expression of MCU, while induced pro-inflammatory polarization and glycolytic metabolism. In contrast, Shikonin increased MCU expression, activated MCU-mediated mCa2+ signal, promoted the polarization of macrophages to anti-inflammatory M2 phenotype, and driven a metabolic shift from glycolysis to oxidative phosphorylation. Either knocking-down MCU expression or pharmacological inhibiting MCU by using RU360 mitigated the effects of Shikonin on Raw 264.7 cells. Furthermore, RU360 counteracted the ameliorative effect of Shikonin on ALI mice. CONCLUSION The current data showed that Shikonin alleviated LPS-induced mice ALI by activating mitochondrial MCU/mCa2+ signal and regulating macrophage metabolism.

Malvidin and its derivatives exhibit potent anti-inflammatory and antioxidant properties, yet their roles and mechanisms in infection-related acute lung injury (ALI) remain unclear. This study aimed to investigate the protective effects of malvidin-3-O-rhamnoside (Mv3rh) in Klebsiella pneumoniae (KP)-induced ALI and to elucidate the underlying mechanisms. A mouse model of KP-induced ALI was employed to assess the effects of Mv3rh on lung pathology, bacterial burden, myeloperoxidase (MPO) activity, alveolar macrophage proportion, cytokine levels, and survival. Mechanistic studies in alveolar macrophages included RNA sequencing, detection of reactive oxygen species (ROS), and evaluation of inflammasome activation, pyroptosis, and antioxidant responses using quantitative PCR (qPCR), Western blotting, flow cytometry, immunoprecipitation, and immunofluorescence. Potential interactions between Mv3rh with NOD-like receptor pyrin domain-containing 3 (NLRP3) or the Toll-like receptor 4/MD-2 complex were examined by molecular docking, cellular thermal shift assay (CETSA), and the interaction with TLR4 was further assessed by surface plasmon resonance (SPR). In vivo, Mv3rh pretreatment significantly mitigated KP-induced ALI, as evidenced by improved lung histopathology, reduced alveolar septal thickening, edema, and neutrophil infiltration, together with improved survival. These protective effects were accompanied by reduced systemic cytokine levels, lower bacterial burdens in the lung and blood, and partial restoration of alveolar macrophage-like cells in bronchoalveolar lavage fluid (BALF). In alveolar macrophages, Mv3rh suppressed TLR4/NF-κB signaling, reduced NLRP3 inflammasome priming and activation, inhibited cleavage of caspase-1 and GSDMD-N, and attenuated macrophage pyroptosis. In addition, Mv3rh activated the NRF2/HO-1 pathway, promoted NRF2 nuclear translocation, and restored antioxidant enzyme activities, including glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT). Mv3rh attenuates inflammation, oxidative stress, and macrophage pyroptosis in KP-induced ALI by regulating the TLR4/NF-κB/NLRP3 inflammasome axis and the NRF2/HO-1 antioxidant pathway. These findings suggest that Mv3rh possesses immunomodulatory activity and may be beneficial in KP-associated ALI.

BACKGROUND Sepsis-induced acute lung injury (ALI) and intestinal injury were characterized by dysregulated systemic inflammation and organ dysfunction. Host-directed therapy (HDT) that modulates excessive immune responses is a promising complementary strategy. Salvianolic acid B (Sal B) has been reported to modulate various signaling pathways, yet whether it targets TNFR1 to simultaneously inhibit NF-κB, necroptosis, and p-MLCK/p-MLC2 in septic ALI remains unexplored. PURPOSE This study aimed to investigate the protective effects of Sal B against sepsis-induced lung-intestine injury and to elucidate its underlying molecular mechanisms, with a focus on identifying its potential cellular target. METHODS A murine model of sepsis-induced ALI was established via lipopolysaccharide (LPS) challenge. H&E staining, ELISA, immunohistochemistry analyses were performed to assess lung, intestinal injury and their barrier damage. In vitro, models of LPS/zVAD-induced macrophage necroptosis and tumor necrosis factor-α (TNF-α) induced epithelial barrier damage were established in J774A.1, THP-1, A549, and HCT116 cells. Cell death, cytokine secretion, the key proteins of necroptosis and signal molecules related to epithelial barrier integrity were evaluated using LDH/PI assays, ELISA, western blotting, and immunofluorescence. By using gene silencing and overexpression techniques, the role of tumor necrosis factor receptor 1 (TNFR1) in regulating the necrotic apoptosis process of macrophages infected with LPS was elucidated. The Sal B-TNFR1 potential interaction was validated using drug target identification methods such as molecular docking and site-directed mutagenesis. RESULTS In vivo, Sal B alleviated pulmonary edema, histopathological damage in lung and colon, and reduced systemic and local levels of TNF-α and interleukin-1β (IL-1β). It concurrently suppressed the activation of the phospho myosin light-chain kinase/phospho myosin light chain 2 (p-MLCK/p-MLC2) pathway and restored expression of tight junction proteins, while inhibiting the necroptosis pathway. In vitro, Sal B inhibited TNF-α-induced barrier damage in epithelial cells and LPS/zVAD-induced necroptosis in macrophages. Mechanistically, Sal B exhibits a strong binding potential with TNFR1 and may exert protective effects by targeting TNFR1 to modulate necroptosis and pulmonary and intestinal epithelial barrier damage, ultimately attenuating LPS-induced the lung-intestine injury. CONCLUSION By potentially targeting TNFR1, Sal B exerts protective effects on both lung and intestine. These findings underscore the therapeutic potential of Sal B as a novel HDT strategy.

Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions characterized by excessive inflammation, alveolar-capillary barrier disruption, and immunothrombosis. Mortality remains persistently high due to the lack of effective targeted therapies. Emerging evidence indicates that histone post-translational modifications (PTMs) play dual regulatory roles by modulating intranuclear gene transcription and, upon extracellular release, amplifying damage-associated molecular pattern (DAMP) signaling. Scope This review proposes a unified pathological framework termed the “Nuclear Epigenetic Remodeling‒Extracellular DAMP Amplification Circuit.” By conceptualizing this as an inside-out pathological cascade, we integrate four principal histone modifications—acetylation, methylation, lactylation, and citrullination—and evaluate three-tiered therapeutic strategies alongside the unique multi-target potential of traditional Chinese medicine (TCM). Key Findings Mechanistically, intranuclear HDAC3/6 drive inflammatory gene expression and pyroptosis, while cytoprotective SIRT1/3/6 suppress inflammasome activation and ferroptosis; concurrently, histone lactylation at H3K18 and H3K14 bridges glycolytic metabolism with ferroptosis and glycocalyx degradation; ultimately, externalized citrullinated histone H3 (CitH3) propagates a thrombo-inflammatory cascade driving NET-mediated immunothrombosis. Corresponding to this cascade, TCM-derived interventions collectively show promising potential to act across all therapeutic tiers by modulating the HDAC/SIRT acetylation axis, suppressing the PAD4–CitH3–NETs cascade, and regulating lactylation-linked metabolic pathways. Conclusion We propose a precision medicine approach integrating dynamic epigenetic biomarkers (eg, serum CitH3 and H3K18la) with a multi-tiered intervention framework. This paradigm aims to shift ALI/ARDS treatment from empirical supportive care toward mechanism-based, individualized targeted therapies.

Acute lung injury (ALI) is a life‐threatening inflammatory disease of the respiratory system, characterised by high mortality rates and lack of effective clinical interventions. Emerging evidence suggests that traditional Chinese medicine (TCM) formulations may offer therapeutic benefits in managing inflammatory respiratory diseases. Jinbei decoction (JBD), a 12‐herb TCM preparation currently used for pulmonary fibrosis, has shown preliminary therapeutic potential in ALI; however, mechanistic studies remain limited. This study systematically evaluated JBD's therapeutic efficacy and elucidated its molecular mechanisms in LPS‐induced ALI. Survival analysis demonstrated that JBD significantly improved survival rates in a concentration‐dependent manner, while histopathological evaluation revealed a marked reduction in pulmonary tissue damage. These effects were further supported by significant decreases in circulating levels of major pro‐inflammatory cytokines, such as TNF‐α, IL‐6 and IL‐1β. Network pharmacology analysis identified 111 molecular targets associated with ALI pathogenesis influenced by JBD components, highlighting the regulatory effect on inflammatory signalling pathways in macrophages as the key intervening mechanism. Specifically, JBD suppressed LPS‐induced inflammatory responses by inhibiting ERK phosphorylation and blocking IKKα/β activation, thereby preventing NF‐κB‐dependent cytokine production in macrophages. Notably, astrapterocarpan was identified as the primary bioactive constituent of JBD through integrated network pharmacology and biochemical analyses. It was found to directly destabilise TRAF6 protein and to exhibit therapeutic efficacy comparable to that of dexamethasone in promoting histological recovery. In vivo experiments further confirmed that JBD significantly reduced TRAF6 expression in murine models, reinforcing the conclusion that its therapeutic effects are predominantly mediated by astrapterocarpan. Collectively, these findings suggest that JBD functions as an agent capable of regulating macrophage polarisation and mitigating cytokine storm through TRAF6‐dependent signalling pathways, thereby providing a mechanistic basis for its potential clinical application in inflammatory lung diseases.

Background Acute lung injury (ALI) is a life-threatening inflammatory disease without effective therapeutic regimen. Macrophage polarization plays a key role in the initiation and resolution of pulmonary inflammation. Therefore, modulating macrophage phenotype is a potentially effective way for acute lung injury. Cryptotanshinone (CTS) is a lipophilic bioactive compound extracted from the root of Salvia miltiorrhiza with a variety of pharmacological effects, especially the anti-inflammatory role. In this study, we investigated the therapeutic and immunomodulatory effects of CTS on ALI. Materials and methods The rat model of ALI was established by intratracheal instillation of LPS (5 mg/kg) to evaluate the lung protective effect of CTS in vivo and to explore the regulation of CTS on the phenotype of lung macrophage polarization. LPS (1 μg/mL) was used to stimulate RAW264.7 macrophages in vitro to further explore the effect of CTS on the polarization and metabolic reprogramming of RAW264.7 macrophages and to clarify the potential mechanism of CTS anti-ALI. Results CTS significantly improved lung function, reduced pulmonary edema, effectively inhibited pulmonary inflammatory infiltration, and alleviated ALI. Both in vivo and in vitro results revealed that CTS inhibited the differentiation of macrophage into the M1 phenotype and promoted polarization into M2 phenotype during ALI. Further in vitro studies indicated that CTS significantly suppressed LPS-induced metabolic transition from aerobic oxidation to glycolysis in macrophages. Mechanistically, CTS blocked LPS-induced metabolic transformation of macrophages by activating AMPK. Conclusion These findings demonstrated that CTS regulates macrophage metabolism by activating AMPK, and then induced M1-type macrophages to transform into M2-type macrophages, thereby alleviating the inflammatory response of ALI, suggesting that CTS might be a potential anti-ALI agent.

… antipyretic, analgesic, and immunomodulatory effect in traditional Chinese medicine. This study was … These results suggested that the effect of BCPs against ALI might be related with its …

Background Bupleurum polysaccharides (BPs), isolated from Bupleurum smithii var. parvifolium, possesses immunomodulatory activity, particularly on inflammation. Bacterial endotoxin lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor 4 (TLR4) on host cell membrane. The present study was performed to evaluate whether the therapeutic efficacy of BPs on suppression of LPS’s pathogenecity could be associated with the modulating of TLR4 signaling pathway. Methodology/Principal Findings LPS stimulated expression and activation of factors in the TLR4 signaling system, including TLR4, CD14, IRAK4, TRAF6, NF-κB, and JNK, determined using immunocytochemical and/or Western blot assays. BPs significantly inhibited these effects of LPS. LPS increased pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-12p40, and IFN-β) and NO production, evaluated using ELISA and Griess reaction assays, respectively. BPs antagonized these effects of LPS. Interestingly, BPs alone augmented secretion of some pro-inflammatory cytokines of non-LPS stimulated macrophages and enhanced phagocytic activity towards fluorescent E.coli bioparticles. In a rat model of acute lung injury (ALI) with pulmonary hemorrhage and inflammation, BPs ameliorated lung injuries and suppressed TLR4 expression. Significance The therapeutic properties of BPs in alleviating inflammatory diseases could be attributed to its inhibitory effect on LPS-mediated TLR4 signaling.

… (ALI) remains a formidable clinical challenge due to its multifaceted inflammatory pathology and limited treatment … as a promising strategy for ALI treatment by enhancing mitochondrial …

Infectious diseases caused by viruses or bacteria pose a serious threat to human life and health system, such as influenza, COVID‐19, and sepsis. They are characterized by obstacles of pathogen clearance, immune dysfunction, or microbial dysbiosis. Conventional therapies are facing tremendous challenges such as antibiotic resistance and viral rapid mutations. Chinese herbal medicine‐derived extracellular vesicles‐like particles (CHM‐EVLPs), a novel strategy, have exhibited great potential for infectious disease therapy. These natural CHM‐EVLPs possess unique advantages in clearing pathogens, orchestrating host immune homeostasis, repairing tissue barrier, and mitigating microbial dysbiosis. Besides, they can deliver some therapeutic drugs for targeted therapy as nano carriers. Good biocompatibility and organotropism also endowed them satisfactory security. These advantages might assist CHM‐EVLPs overcome the limitations of traditional therapeutics. Thus, this review first summarizes the basic information of CHM‐EVLPs regarding preparation methods and bioactive components. Then, the pathological mechanisms of infectious diseases and the protective effects of CHM‐EVLPs through interaction with these mechanisms will be comprehensively discussed. Finally, future perspectives of CHM‐EVLPs for infectious diseases treatment are proposed. Overall, as a bridge connecting traditional herbal medicine and nanotechnology, CHM‐EVLPs offer a high‐efficiency, sustainable, and multitarget approach to treat infectious diseases.

The immunomodulatory potential of Lycium barbarum polysaccharides (LBP) is well-established, yet the intricate structure-activity relationships (SAR) underlying these effects require clarification to advance therapeutic applications. This review synthesizes current knowledge on how specific structural parameters of LBP, including molecular weight, monosaccharide composition, glycosidic linkage types, and chemical modifications influence its immunoregulatory functions. Key findings reveal a non-linear dependence of LBP’s immunomodulatory activity on molecular weight. Fractions within the medium molecular weight range (105–106 Da) often demonstrate optimal efficacy, which is attributed to their capacity for facilitating multivalent binding to pattern recognition receptors (PRRs). Furthermore, a high content of arabinose and galactose is a critical structural determinant, with arabinogalactan-like motifs serving as key recognition elements for immune cell activation. Mechanistically, LBP orchestrates immune responses through multi-target pathways. It directly modulates macrophage polarization via the STAT1/STAT6 pathways, promotes dendritic cell maturation through NF-κB and Notch signaling, and influences T-cell differentiation. Concurrently, LBP exerts indirect immunomodulatory effects via the gut microbiota-immune axis by enriching beneficial bacteria and their immunoregulatory metabolites, such as short-chain fatty acids. Despite robust preclinical evidence, clinical translation is hampered by the heterogeneity of LBP preparations. This review underscores the necessity of standardizing LBP based on SAR insights to develop precision immunomodulators for therapeutic applications.

In humans, the immune system serves as a protective barrier against infection; however, when the immune system is out of balance, it can harm the host. Immunomodulators are chemicals or medications that have been employed in the clinic to treat an unbalanced immune response. The majority of immunological medicines in clinical use are cytotoxic. They harm the patient's quality of life by causing various side effects and being associated with higher production costs, longer lead times, and a high failure rate. Furthermore, obtaining single-compound chemicals with low toxicity, high efficacy, and selectivity for specified disorders is difficult for researchers. As a result, techniques based on alternative medicine are gaining attraction in drug development, focusing on innovative natural compounds utilized to treat various disorders. Many plant molecules founded to have biologically beneficial properties. This review aimed to look at the immunomodulatory activity of plant-derived chemicals from widely-used plants.  

BackgroundOcimum species (Lamiaceae) has been traditionally used for treatment of upper respiratory tract infections, bronchitis, coughs, sore throat, and wound healing. The Immunomodulatory and anti-inflammatory effects of hydro-ethanolic extract of Ocimum basilicum (O. basilicum) leaves was examined in ovalbumin sensitized animals.MethodsWistar rats were divided to six groups; non-sensitized, sensitized to ovalbumin, sensitized and treated with dexamethasone (1.25 μg/mL), and O. basilicum extract (0.75, 1.50 and 3.00 mg/mL) in drinking water for 21 days. The levels of interleukin 4 (IL-4), interferon gamma (IFN-γ), IFN-γ/IL-4 ratio, immunoglobulin E (IgE), phospholipase A2 (PLA2) and total protein (TP) in BALF, and lung pathological changes were examined.ResultsA significant increase in IL-4, IgE, PLA2 and TP levels, all lung pathological indices as well as significant decrease in IFN-γ/IL-4 ratio was seen in the asthmatic compared to the control rats (P < 0.05 to P < 0.001). Treatment with O. basilicum extract resulted in decreased IL-4, IgE, PLA2 and TP levels, but increased IFN-γ/IL-4 ratio compared to untreated sensitized rats (P < 0.01 to P < 0.001). The plant significantly improved the pathological changes of sensitized rats (P < 0.05 to P < 0.01). The improvement effects of higher concentrations of the O. basilicum extract were significantly more than those of dexamethasone (P < 0.05 to P < 0.001).ConclusionThe improvement effects of O. basilicum on pathological changes, immunological and inflammatory markers in sensitized rats comparable or even more potent than dexamethasone suggests the therapeutic potential of the plant in asthma.

Jian-Ti-Kang-Yi decoction (JTKY) is widely used in the treatment of COVID-19. However, the protective mechanisms of JTKY against pneumonia remain unknown. In this study, polyinosinic-polycytidylic acid (poly(I:C)), a mimic of viral dsRNA, was used to induce pneumonia in mice; the therapeutic effects of JTKY on poly(I:C)-induced pneumonia model mice were evaluated. In addition, the anti-inflammatory and anti-oxidative potentials of JTKY were also investigated. Lastly, the metabolic regulatory effects of JTKY in poly(I:C)-induced pneumonia model mice were studied using untargeted metabolomics. Our results showed that JTKY treatment decreased the wet-to-dry ratio in the lung tissue, total protein concentration, and total cell count of the bronchoalveolar lavage fluid (BALF). Hematoxylin and Eosin (HE) and Masson staining indicated that the JTKY treatment alleviated the pathological changes and decreased the fibrotic contents in the lungs. JTKY treatment also decreased the expression of pro-inflammatory cytokines [interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α)] and increased the levels of immunomodulatory cytokines (IL-4 and IL-10) in the BALF and serum. Flow cytometry analysis showed that the JTKY treatment lowered the ratio of CD86+/CD206+ macrophages in the BALF, decreased inducible nitric oxide synthase (iNOS) level, and increased arginase 1 (Arg-1) level in lung. JTKY also lowered CD11b+Ly6G+ neutrophils in BALF and decreased myeloperoxidase (MPO) activity in lung. Moreover, it also elevated superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and decreased methane dicarboxylic aldehyde (MDA) level in lung. Untargeted metabolomic analysis showed that the JTKY treatment could affect 19 metabolites in lung, such as L-adrenaline, L-asparagine, ornithine, and alpha-ketoglutaric acid. These metabolites are associated with the synthesis and degradation of ketone bodies, butanoate, alanine, aspartate, and glutamate metabolism, and tricarboxylic acid (TCA) cycle processes. In conclusion, our study demonstrated that treatment with JTKY ameliorated poly(I:C)-induced pneumonia. The mechanism of action of JTKY may be associated with the inhibition of the inflammatory response, the reduction of oxidative stress, and the regulation of the synthesis and degradation of ketone bodies, TCA cycle, and metabolism of alanine, aspartate, glutamate, and butanoate processes in lung.

ETHNOPHARMACOLOGICAL RELEVANCE Acute lung injury (ALI) lacks effective therapies. HIF-1α-driven glycolysis can promote histone lactylation and sustain pro-inflammatory (M1) macrophage responses. Daxiefei Decoction (DXFD), a classic traditional Chinese medicine formula, is used for pulmonary inflammatory diseases, but its immunometabolic mechanism remains unclear. AIM OF THE STUDY To evaluate the protective efficacy of DXFD against lipopolysaccharide (LPS)-induced ALI and to determine whether it acts through the HIF-1α/glycolysis/histone H3K18 lactylation (H3K18la) axis to regulate macrophage polarization. MATERIALS & METHODS DXFD constituents were characterized by UPLC-LTQ-Orbitrap-MS/MS, followed by network pharmacology, molecular docking, and molecular dynamics (MD) simulations. Lung transcriptomics and metabolomics were performed in ALI mice. Efficacy and mechanisms were assessed in LPS-challenged mice and RAW264.7 macrophages using histopathology, ELISA, qRT-PCR, Western blotting, and immunofluorescence. HIF-1α overexpression was used for validation. RESULTS DXFD dose-dependently alleviated lung injury and reduced pro-inflammatory cytokines in vivo, and suppressed M1 polarization in vivo and in LPS-stimulated macrophages. Multi-omics indicated activation of HIF-1α-associated inflammatory and glycolytic programs in ALI, which were normalized by DXFD. DXFD decreased glycolytic enzyme expression and reduced histone H3K18 lactylation (H3K18la); these effects were partially reversed by HIF-1α overexpression. Molecular docking and dynamics suggested stable binding of baicalin to HIF-1α. CONCLUSIONS DXFD mitigates ALI by dampening HIF-1α-dependent glycolysis and H3K18la, thereby restraining M1-driven inflammatory amplification.

Severe pneumonia-associated lung injury remains a critical focus in infection and immunology research due to its high lethality and complex immunopathology. Affected patients often present with cellular immune deficiency and an imbalanced interplay between pro-inflammatory and anti-inflammatory mediators, with infection-immunity disequilibrium driving disease progression. The initial infection triggers a defense-injury cascade: while inflammation facilitates pathogen clearance, persistent or excessive activation leads to progressive lung tissue damage. Recent advances have deepened our understanding of immune mechanisms and inflammatory regulation; however, key challenges persist in clinical translation. Here, we synthesize current evidence on the immunopathology of severe pneumonia-associated lung injury, dissect the hierarchical architecture of its molecular regulatory networks, and critically appraise existing therapeutic strategies and their limitations. We propose a translational framework—encompassing mechanistic research, network modelling, and precision intervention—to guide stage-specific regulation and targeted therapy. Finally, we outline the major challenges impeding the clinical application of basic immunological discoveries and highlight future directions for improving patient outcomes.

Trained immunity refers to a form of nonspecific immunological memory established through epigenetic modifications and metabolic reprogramming in innate immune cells following stimulation. This concept offers a novel framework for understanding and treating respiratory diseases. Chronic inflammation and dysregulated immune memory resulting from respiratory immune imbalance underlie many respiratory conditions, including infectious pneumonia, asthma, and chronic obstructive pulmonary disease (COPD). The core mechanisms of trained immunity involve epigenetic regulation-mediated by histone modifications such as histone H3 lysine 4 trimethylation (H3K4me3)-and metabolic reprogramming, exemplified by glycolysis. Trained immunity exhibits a "double-edged sword" effect in respiratory diseases: appropriate activation enhances pathogen clearance, whereas excessive activation may lead to sustained inflammation and tissue damage. Intervention strategies targeting trained immunity-such as vaccine-induced training, metabolic modulation, and natural product application-have shown clinical promise. However, the field faces challenges, including a lack of specific regulatory approaches and clinically applicable biomarkers. Future efforts should focus on deepening mechanistic insights and facilitating the clinical translation of precise interventions, thereby opening new paradigms for the prevention and treatment of respiratory diseases.

Sepsis-induced acute lung injury (SALI) is characterized by a dysregulated inflammatory and immune response. As a key component of the innate immune system, macrophages play a vital role in SALI, in which a macrophage phenotype imbalance caused by an increase in M1 macrophages or a decrease in M2 macrophages is common. Despite significant advances in SALI research, effective drug therapies are still lacking. Therefore, the development of new treatments for SALI is urgently needed. An increasing number of studies suggest that natural products (NPs) can alleviate SALI by modulating macrophage polarization through various targets and pathways. This review examines the regulatory mechanisms of macrophage polarization and their involvement in the progression of SALI. It highlights how NPs mitigate macrophage imbalances to alleviate SALI, focusing on key signaling pathways such as PI3K/AKT, TLR4/NF-κB, JAK/STAT, IRF, HIF, NRF2, HMGB1, TREM2, PKM2, and exosome-mediated signaling. NPs influencing macrophage polarization are classified into five groups: terpenoids, polyphenols, alkaloids, flavonoids, and others. This work provides valuable insights into the therapeutic potential of NPs in targeting macrophage polarization to treat SALI. This paper reviews the characteristics of macrophage polarization and explores the signaling pathways that regulate polarization phenotypes. This paper reviews the changes in macrophage phenotypes and their regulatory mechanisms during the three stages of sepsis-induced lung injury: the overwhelming inflammatory phase, the immunosuppressive phase, and the fibrotic phase. This paper reviews natural compounds with potential therapeutic effects on macrophage polarization-related sepsis-associated lung injury (SALI) and explores their mechanisms of action against SALI. This paper reviews the characteristics of macrophage polarization and explores the signaling pathways that regulate polarization phenotypes. This paper reviews the changes in macrophage phenotypes and their regulatory mechanisms during the three stages of sepsis-induced lung injury: the overwhelming inflammatory phase, the immunosuppressive phase, and the fibrotic phase. This paper reviews natural compounds with potential therapeutic effects on macrophage polarization-related sepsis-associated lung injury (SALI) and explores their mechanisms of action against SALI.

Macrophages are critical mediators of the innate immune response against foreign pathogens, including bacteria, physical stress, and injury. Therefore, these cells play a key role in the “inflammatory pathway” which in turn can lead to an array of diseases and disorders such as autoimmune neuropathies and myocarditis, inflammatory bowel disease, atherosclerosis, sepsis, arthritis, diabetes, and angiogenesis. Recently, more studies have focused on the macrophages inflammatory diseases since the discovery of the two subtypes of macrophages, which are differentiated on the basis of their phenotype and distinct gene expression pattern. Of these, M1 macrophages are pro-inflammatory and responsible for inflammatory signaling, while M2 are anti-inflammatory macrophages that participate in the resolution of the inflammatory process, M2 macrophages produce anti-inflammatory cytokines, thereby contributing to tissue healing. Many studies have shown the role of these two subtypes in the inflammatory pathway, and their emergence appears to decide the fate of inflammatory signaling and disease progression. As a next step in directing the pro-inflammatory response toward the anti-inflammatory type after an insult by a foreign pathogen (e. g., bacterial lipopolysaccharide), investigators have identified many natural compounds that have the potential to modulate M1 to M2 macrophages. In this review, we provide a focused discussion of advances in the identification of natural therapeutic molecules with anti-inflammatory properties that modulate the phenotype of macrophages from M1 to M2.

… bidirectional M1/M2 transitions contribute to inflammatory … levels of M1 and M2 polarization, promoting a balanced state … M1 polarization and alleviates sepsis-induced acute lung …

The plant kingdom is a source of important therapeutic agents. Therefore, in this review, we focus on natural compounds that exhibit efficient anti-inflammatory activity via modulation signaling transduction pathways in macrophage cells. Both extracts and pure chemicals from different species and parts of plants such as leaves, roots, flowers, barks, rhizomes, and seeds rich in secondary metabolites from various groups such as terpenes or polyphenols were included. Selected extracts and phytochemicals control macrophages biology via modulation signaling molecules including NF-κB, MAPKs, AP-1, STAT1, STAT6, IRF-4, IRF-5, PPARγ, KLF4 and especially PI3K/AKT. Macrophages are important immune effector cells that take part in antigen presentation, phagocytosis, and immunomodulation. The M1 and M2 phenotypes are related to the production of pro- and anti-inflammatory agents, respectively. The successful resolution of inflammation mediated by M2, or failed resolution mediated by M1, may lead to tissue repair or chronic inflammation. Chronic inflammation is strictly related to several disorders. Thus, compounds of plant origin targeting inflammatory response may constitute promising therapeutic strategies.

Viral pneumonia, primarily caused by influenza viruses, coronaviruses, and other respiratory pathogens, is characterized by direct alveolar epithelial injury and an excessive immune response, leading to severe inflammation, oxidative stress, and, in critical cases, acute respiratory distress syndrome and multi-organ failure. Traditional Chinese Medicine (TCM), widely employed in China for both the prevention and treatment of viral pneumonia, provides multitarget and broad-spectrum therapeutic benefits with low toxicity and minimal side effects, offering a promising alternative to conventional antiviral therapies. Recent studies have demonstrated that natural products derived from TCM, including flavonoids, polyphenols, polysaccharides, and terpenoids, can effectively modulate immune and oxidative stress responses by targeting multiple signaling pathways. In this review, we conducted a systematic literature search in PubMed, Web of Science, and SciFinder databases, focusing primarily on studies published over the past decade. Keyword combinations included “viral pneumonia,” “Traditional Chinese Medicine,” “natural products,” “inflammation,” and “oxidative stress,” in addition to mechanism-related terms such as “NF-κB,” “Nrf2,” “PI3K/Akt,” “MAPK,” and “NLRP3 inflammasome.” Natural compounds acting on these pathways have been shown to suppress cytokine storms, reduce reactive oxygen species accumulation, preserve alveolar epithelial integrity, and alleviate pulmonary inflammation. This review highlights the latest progress in understanding how natural products exert protective effects in viral pneumonia through the modulation of inflammation and oxidative stress–related pathways. These findings provide a theoretical foundation for developing novel anti-inflammatory and antioxidant therapeutic strategies based on natural medicines for the treatment of viral respiratory diseases.

Macrophage polarization plays a vital role in regulating inflammation, and the balance of this process is crucial for maintaining tissue health and influencing disease progression. Recent studies have shown how macrophages can adapt their phenotypes in response to their surroundings, underscoring the importance of their polarization changes in various inflammatory conditions, such as infections, tumors, metabolic disorders, and autoimmune diseases. This review brings together significant advancements in our understanding of the signaling pathways involved in inflammation, the role of epigenetic factors, metabolic changes, and the development of targeted therapies, with the goal of offering new perspectives on treating inflammation-related diseases.

… of this regulatory balance through sustained pro-inflammatory … candidate for acute lung injury [78]. Curcumin, extensively … into pro-inflammatory M1 or anti-inflammatory M2 phenotypes …

Acute Respiratory Distress Syndrome is a familiar and destructive clinical condition characterized by progressive, swift and impaired pulmonary state. It leads to mortality if not managed in a timely manner. Recently the role of imbalanced macrophage polarization has been reported in ARDS. Macrophages are known for their heterogeneity and plasticity. Under different microenvironmental stimuli, they (M0) can switch between classically activated macrophage (M1) and alternatively activated (M2) states. This switch is regulated by several signaling pathways and epigenetic changes. In this review, the importance of macrophage M1 and M2 has been discussed in the arena of ARDS citing the phase-wise impact of macrophage polarization. This will provide a further understanding of the molecular mechanism involved in ARDS and will help in developing novel therapeutic targets. Various biomarkers that are currently used concerning this pathophysiological feature have also been summarized.

… by various oxidative and inflammatory signals. Consequently… cellular response against inflammatory response and … pro-inflammatory M1 macrophages and anti-inflammatory M2 …