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Introduction

Acute lung injury (ALI) is a severe respiratory disease caused by uncontrolled acute inflammation of the lungs caused by various direct factors (such as severe lung infection, pulmonary embolism and lung injury) and indirect factors (such as sepsis, trauma and massive blood transfusions), resulting in impaired lung function. It can further develop into acute respiratory distress syndrome (ARDS) characterized by progressive respiratory distress and refractory hypoxemia (1). According to a study involving 459 intensive care units (ICUs) from 50 countries on 5 continents during 4 consecutive weeks in winter 2014, the prevalence of ARDS accounted for 10.4% of ICU admissions. This survey found that a total of 2,377 patients developed ARDS within the first 48 h of acute hypoxic respiratory failure, with 30.0% of patients presenting with mild ARDS, 46.6% of patients with moderate ARDS and 23.4% of patients with severe ARDS. The in-hospital mortality rate for ARDS was 34.9% in mild patients, 40.3% in moderate patients and 46.1% in patients with severe ARDS (2). Pathological features of ALI include diffuse alveolar damage and large aggregates of neutrophils in lung tissue, which produce and secrete pro-inflammatory cytokines (3). This causes an uncontrolled inflammatory response, extensive apoptosis of lung epithelial cells, alveolar defects, impaired barrier function of capillary membranes and alveoli, and invasion of proteolytic edema fluid into the alveoli, which destroys surface cellular structures (4,5). However, the pathogenesis of ALI/ARDS is complex, and there is currently no effective, specific treatment in clinical practice. Therefore, innovative mechanisms and therapies are urgently needed to alter the onset and outcome of ALI/ARDS.

Numerous immune cells, such as neutrophils, lung macrophages, alveolar epithelial cells (AECs) and T cells, are involved in the development of ALI/ARDS, which involves the interaction between lung structures and a complex immune cell microenvironment that is essential for ALI/ARDS (6). Macrophages are the main cell type in innate immunity (7). They are widely distributed in the lung microenvironment, have a wide range of plasticity and respond to different stimuli to convert phenotypes (8). Therefore, lung macrophages, as the main effector cells in the lungs and play different roles at different stages of ALI/ARDS (9). Macrophages exacerbate ALI/ARDS by promoting the polarization of pro-inflammatory macrophages and the release of their products, decreasing the release of anti-inflammatory macrophages and their products, and inducing macrophage pyroptosis (10,11). In addition, by decreasing the phagocytosis of macrophages, increasing apoptosis can also promote ALI/ARDS (11). A relevant article has summarized existing and new drugs that have been tested or are currently being clinically tested for the treatment of ALI and ARDS, and different data may support the selective use of neuromuscular blocking agents, corticosteroids and neutrophil elastase inhibitors for the treatment of ARDS (12). However, these are not yet universally available (12). Data from patients with coronavirus disease (COVID) associated ALI /ARDS support using IL-6 monoclonal antibodies, corticosteroids and Janus kinase (JAK) inhibitors to treat this condition (12). Relatively few drugs that target macrophages are available for the treatment of ALI/ARDS (13). IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) are important cytokines involved in the activation of monocytes and the induction of their differentiation into macrophages (14). In clinical practice, lung inflammation in patients with COVID-19 can be reduced using GM-CSF inhibitors (such as sargramostim and mavrilimumab), which directly target GM-CSF and block its interaction with macrophage surface receptors (15). However, this is only a preventive strategy and has no therapeutic effect on ARDS (16). Homeostatic effects of GM-CSF in the lungs and the blockade of GM-CSF in patients with COVID-19 have the potential risk of impairing alveolar macrophage function and impeding pathogen clearance (17). In previous years, preclinical studies have found that the use of natural compounds isolated from herbal medicine can effectively improve ALI/ARDS by regulating macrophage polarization and pyroptosis (18–20). Furthermore, several natural products also function by regulating phagocytosis and autophagy (21–23). In the present review, the natural products that have been shown to regulate macrophage abnormalities in ALI/ARDS within the past five years and their mechanisms of action are introduced. These products may undergo clinical trials and become potential drugs that treat ALI/ARDS by targeting macrophages, providing new ideas and further research directions for the development of ALI/ARDS therapeutic drugs.

Natural products that modulate macrophage polarization

Macrophages are heterogeneous and highly plastic immune cells that recognize pathogen-associated molecular patterns and trigger innate immune responses to activate host defenses and play a regulatory role in inflammatory responses (24). Under different stimuli, macrophages can polarize into two different subtypes, specifically the M1 macrophages (possessing pro-inflammatory characteristics) and the M2 macrophages (possessing properties that counter inflammation) (25). An imbalance in the polarization of the macrophages leads to an inflammatory response (26). Studies have found that balancing M1/M2 macrophages is beneficial to eliminate the inflammatory storm that occurs in ALI/ARDS, which enhances recovery (27–29). The natural products that may be used for the treatment of ALI/ARDS, which modulate macrophage polarization, are summarized in Table I and Fig. 1.

Table I. Natural products that modulate macrophage polarization

Figure 1. Molecules of natural products interfering with macrophage polarization. Created using BioRender.com. ↑ indicates promotion and ⊥ indicates inhibition. PPARγ, peroxisome proliferator-activated receptor γ; Nrf2, nuclear factor erythroid 2-related factor 2; α7nAChR, α7 nicotinic acetylcholine receptor; Erg-1, early growth response 1; NLRP3, pyrin domain-containing protein 3; Trem2, triggering receptor expressed on myeloid cells; GSDMD, gasdermin D; TLR4, Toll-like receptor 4; STAT3, signal transducer and activator of transcription 3; IRF4, interferon regulatory factor 4; FBXW7, F-box and WD repeat domain containing 7; HIF, hypoxia-inducible factor; SOCS3, suppressor of cytokine signaling 3; G9a, euchromatic histone-lysine N-methyltransferase 2; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; ERK, extracellular regulated protein kinases; Egr-1, early growth response 1; JNK, c-Jun N-terminal kinase; PKM2, pyruvate kinase M2; AMPK, adenosine 5′-monophosphate-activated protein kinase; NFACT1, nuclear factor of activated T cells 1; STRT1, silent information regulator 1.

M1 macrophage polarization

Macrophage polarization plays an important role in the development of ALI/ARDS (10). In the early stages of ALI, pro-inflammatory (M1) macrophages predominate (27). Macrophages are usually polarized into the M1 subtype by Th1-related cytokines, such as IFN-γ and TNF-α, as well as through lipopolysaccharide (LPS) stimulation (30). These macrophages produce higher levels of TNF-α, IL-1, IL-6, IL-12, chemokine CC motif chemokine ligand 8, IL-23, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 2, reactive oxygen species (ROS) and cyclooxygenase 2 (31). In addition, they strongly express CD16 and CD32 (28,31), thereby promoting lung inflammation. Functionally, this macrophage population is primarily involved in pro-inflammatory processes, chemotaxis, free radical formation, matrix degradation, antimicrobial activities and antitumor activities (32). When an inflammatory response occurs in the lungs, peripheral monocytes are recruited into the lung and undergo differentiation into pro-inflammatory macrophages, which modulate the inflammatory response (33). An analysis of bronchoalveolar lavage fluid (BALF) from patients with mild or severe COVID-19 showed that high levels of MCP-1/CCL2 recruit monocytes from the blood into the lungs, which differentiate into pro-inflammatory macrophages (34). Monocytic phagocytes account for 80% of the total cell count of BALF (34). In addition, the exosomal miR-30d-5p of neutrophils promotes M1 polarization in macrophages and initiates macrophage pyroptosis in sepsis-related ALI (35). Induced mitochondrial fusion can target the IκK/IκB/NF-κB pathway in RAW264.7 cells and inhibit M1 macrophage phenotypic switching in LPS-induced ALI (36).

Certain natural products have been found to attenuate ALI/ARDS by inhibiting the polarization of M1 macrophages (28). 5-Methoxyflavone activates nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which reduces the activation of signal transducer and activator of transcription (STAT)1 signaling, and blocks the LPS/IFN-γ-induced M1 polarization and M2 repolarization with an M1 phenotype in RAW264.7 cells; this protects RAW264.7 cells stimulated by LPS (37). Taraxasterol protects LPS-induced ALI in rats by decreasing the polarization of M1 macrophages and decreasing the levels of inflammatory cytokines (38). Abietic acid improves survival and attenuates sepsis-induced lung injury in mice; both in vitro and in vivo studies have suggested that abietic acid inhibits inflammation and M1 macrophage polarization, and activates the NF-κB pathway (39). This may be the mechanism through which abietic acid attenuates sepsis-induced lung injury (39). Hederagenin exerts anti-inflammatory effects in ALI by inhibiting the NF-κB signaling pathway in vivo and in vitro, thereby inhibiting M1 macrophage polarization (40). Salidroside can reduce the expression of the inflammatory cytokines, high-mobility group box 1 (HMGB1) and keratin 14, and has a significant therapeutic effect on the ALI/ARDS rat model (41). In addition, it is involved in the regulation of LPS-induced alveolar macrophage (AM) inflammatory activation by AECs (42). A further study found that salidroside attenuated lung inflammation by inhibiting M1 polarization of JNK/c-Jun-attenuated AMs (43). In LPS-induced ALI/ARDS, Rhein significantly attenuated tissue inflammatory responses and promoted macrophage M2 polarization shift (44). In vitro, Rhein (4,5-dihydroxy-anthraquinone-2-carboxylic acid) reduced intracellular ROS levels and activated P65, thereby attenuating M1 polarization in macrophages (44). Mechanistically, Rhein exerted its protective effect against LPS-induced ALI/ARDS by targeting the nuclear factor of activated T cells 1 (NFATc1)/triggering receptor expressed on myeloid cells 2 (Trem2) axis, which was significantly attenuated in both Trem2 and NFATc1 blockade assays (44). Rhein intervenes in the metabolic reprogramming of macrophages in inflammatory states via Sirtuin 1 (SIRT1), inhibits macrophage activation into pro-inflammatory M1 macrophages, and attenuates LPS damage to mouse lungs and RAW264.7 cells (45). Emodin (anthraquinone compound) demonstrates its therapeutic effects on severe acute pancreatitis (SAP)-ALI by modulating the nucleotide binding oligomerization domain containing-leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3)/caspase 1/gasdermin D (GSDMD) signaling pathway (46). Emodin reduces the production of deleterious pancreatic exosomes under SAP conditions and alters the levels of these pathological exosomes, thereby inhibiting M1 polarization in AMs and cytokine release in the lungs by modulating the peroxisome proliferator-activated receptor γ (PPARγ)/NF-κB pathway (47). In vitro experiments have confirmed that allyl methyl trisulfide inhibits the NF-κB and MAPK pathways, reduces the expression of cyclooxygenase-2 (COX-2) and inducible NO synthase proteins, inhibits M1 polarization in macrophages, and reduces the inflammatory response in LPS-induced ALI (48). 3,4-dihydroxyphenylethyl alcohol glycoside inhibits the activation of NF-κB, STAT3 and p38 MAPK signaling pathways, reduces the polarization of M1 macrophages, and ameliorates CLP-induced inflammation in mice ALI and LPS-induced MH-S cells (49).

M2 macrophage polarization

In the pathological process of advanced pneumonia, the causative factor is eliminated and M1 macrophages are transformed into M2 macrophages, which are activated by Th2 cytokines (such as IL-4 and IL-13) as well as anti-inflammatory cytokines (such as IL-10) and TGF-β (28,50,51). Activated M2 macrophages express low IL-12 and high IL-1 receptor antagonists, chemokine CCL18 and arginase 1 (Arg-1), and are present in inflammatory zone 1 (31). M2 macrophages promote the repair of lung damage by releasing anti-inflammatory cytokines, inhibiting the production of pro-inflammatory mediators, and removing apoptotic neutrophils from the site of inflammation (52). By promoting the activation of M2 macrophages, inflammation can be eliminated, and ALI recovery can be favored (53–55).

A previous study has confirmed that dihydroquercetin alleviates LPS-induced ALI inflammation and apoptosis (56). Dihydroquercetin promotes macrophage M2 polarization through the interferon regulatory factor 4 (IRF4)/miR-132-3p/F-box and WD repeat domain containing 7 axis, inhibits a rise in inflammatory cytokine levels and attenuates LPS-induced lung injury (57). Anisodamine treatment was also found to attenuate LPS-induced lung injury and pulmonary edema by reversing LPS-induced changes in M1 and M2 polarization through the inhibition of G9a-mediated IRF4 silencing in an ALI mouse model (58). In vivo studies have confirmed that resveratrol can reduce the severity of ALI in animal models, while reducing the production of pro-inflammatory cytokines and increasing anti-inflammatory cytokines (59). Resveratrol is a specific SIRT1 activator, and SIRT1 knockout reduces the anti-inflammatory effects of resveratrol (60). In addition, resveratrol may inhibit inflammation by inducing macrophage pyroptosis and apoptosis (61). Resveratrol significantly regulates macrophage activation and polarization by modulating STAT3/suppressor of cytokine signaling 3 (SOCS3) signaling, and it enhances the polarization of anti-inflammatory M2 and CD45+Siglec-F(−) subtype macrophages, thereby inhibiting mouse ALI (62). A study has shown that the activation of SIRT1 by chlorogenic acid can inhibit the acetylation and nuclear translocation of HMGB1, thereby promoting M2 polarization in AMs and alleviating Kp-induced pneumonia (63). Acacetin can reduce LPS damage to RAW 264.7 cells (64) and has been found to significantly improve the survival of ALI mice. It alleviates lung damage by reducing M1 macrophages and promoting the polarization of M2 macrophages on the tumor necrosis factor receptor-associated factor 6/NF-κB/COX-2 axis, thereby inhibiting the production of TNF-α, IL-1β and IL-6 (65). Grape seed proanthocyanidin promotes LPS-induced polarization from M1 to M2a in primary mouse lung macrophages by inhibiting the triggering receptor expressed on myeloid cells 2/PI3K/Akt pathway (66). Tetrahydropalmatine induces the polarization of M1 macrophages to M2 and suppresses inflammation by inhibiting Toll-like receptor 4 (TLR4)/NF-κB/NLRP3 signaling, thereby attenuating ischemia-reperfusion-induced lung injury in rats (67). Dehydrocostus lactone can promote the polarization of M1 macrophages to the M2 phenotype by inhibiting p38 MAPK/NF-κB signaling and activating the AMPK/Nrf2 pathway (68). Ligustrazine can treat ALI/ARDS by inhibiting the TLR4/TRAF/NF-κB/NLRP3/caspase-1 and TLR4/caspase-8/caspase-3 signaling pathways in macrophages, promoting macrophage polarization from M1 to M2 in macrophages, and reducing the pyroptosis of macrophages (54).

In addition, some natural products reduce ALI by decreasing M1 macrophages and increasing M2 macrophages. Luteolin has a protective effect on cecal ligation puncture (CLP)-induced mouse ALI models and LPS-induced cell models by decreasing cytokines and IL-17A, increasing IL-10 levels, reducing M1 macrophage content, and increasing M2 macrophage number (69). Matrine restored sepsis-induced SIRT1 downregulation, and the deacetylation of the NF-κB p65 subunit and p53, thereby inactivating the NF-κB pathway and inhibiting the p53-induced pro-apoptotic pathway in septic lungs (70). It inhibited infiltration by M1 macrophages but increased infiltration by M2 macrophages, thus decreasing the M1 to M2 macrophage ratio in septic lungs (70). Cryptotanshinone inhibited the accumulation of M1 macrophages and increased the accumulation of M2 macrophages in lung tissue (71). A previous study has also suggested that cryptotanshinone regulates the reprogramming of macrophage metabolism by activating AMPK (72). Loganin blocks the ERK and NF-κB pathways to inhibit M1 macrophages, induce M2 activation and inhibit NLRP3 inflammasome-mediated caspase-1 activation by decreasing IL-1β secretion in sepsis-induced ALI (72). Tanshinone IIA has significant anti-inflammatory effects in LPS-stimulated RAW264.7 cell models. It exerts these effects by inhibiting the NLRP3 inflammasome and reducing oxidative stress (73). In vitro assays have also confirmed that tanshinone IIA inhibits the activation of NF-κB and hypoxia-inducible factor pathways, thereby increasing the relative amount of the M2 isoform and decreasing the relative amount of the M1 isoform (73). Iridin reduces glycolysis in LPS-activated macrophages by inhibiting pyruvate kinase M2 (PKM2)-mediated JAK/STAT and NF-κB pathways, reprogramming macrophages from the M1 polarized phenotype to the M2 phenotype and inhibiting the production of pro-inflammatory cytokines (74). Sinomenine reduces TNF-α and IL-6 in LPS-induced bone marrow-derived macrophages (BMDMs) by activating peroxisome proliferator activated receptor β/δ in macrophages (75). In addition, sinomenine inhibits macrophage migration by downregulating Src/FAK/P130Cas activation (76) and inhibits LPS-induced macrophage inflammatory responses by acting on the α7 nicotinic acetylcholine receptor (α7nAChR) (77). A further study found that sinomenine downregulates abnormally high levels of α7nAChR through the α7nAChR/ERK/early growth response 1 feedback pathway, attenuates the M1 phenotype and promotes the M2 phenotype in LPS-stimulated macrophages (78).

In conclusion, in terms of the mechanism of natural products on cell polarization, natural products mainly inhibit the polarization of pro-inflammatory M1 macrophages and promote the transition from M1 to M2 by inhibiting NF-κB, NLRP3, Caspase-1, GSDMD and other signaling pathways, and promoting Nrf2 and AMPK signaling pathways. In addition, it promotes the polarization of anti-inflammatory M2 macrophages by inhibiting STAT1 and SOCS3, and promoting the STAT3 and HIF signaling pathways. In terms of the effects of different types of natural products on macrophage polarization, flavonoids, alkaloids, terpenoids and quinones affect macrophage polarization by inhibiting NF-κB and NLRP3, and activating major signaling pathways such as AMPK.

Natural products that regulate macrophage pyroptosis

Pyroptosis is mediated by programmed cell necrosis by gasdermin (79). It is characterized by the swelling and rupture of cells and the release of pro-inflammatory contents (80). Bacteria, viruses, toxins and drugs (such as chemotherapy drugs paclitaxel and cisplatin, and Anakinra) can cause pyroptosis, which helps to maintain the stability of the internal environment and combat external risk factors (81). There is growing evidence of pyroptosis in different types of lung cells during the development of ALI (81). AMs can respond to external stimuli through pyroptosis in vivo. In vivo studies have found that phenylalanine promotes AM pyroptosis by activating recombinant calcium sensing receptor and initiating the NLRP3 pathway, thereby exacerbating LPS-induced ALI in mice (82). LPS-induced ALI in mice was improved by inhibiting macrophage pyroptosis (83,84). Concurrently, it was found that in LPS-induced ALI in mice, the neutrophil extracellular traps (NETs) formed during neutrophil NETosis may cause macrophage pyroptosis and lead to the deterioration of ALI, while promoting DNA degradation in the NETs (85). In addition, silencing the AIM2 gene may prevent AM pyroptosis (85). 4-Hydroxynonenal, a lipid peroxidation product, has a protective effect on ALI by inhibiting the NLRP3 inflammasome, thereby preventing the activation of caspase-1 and reducing the release of inflammatory cytokines and macrophage pyroptosis (86). The natural products that treat ALI/ARDS by modulating macrophage pyroptosis are summarized in Table II and Fig. 2.

Table II. Natural products that modulate macrophage pyroptosis.

Figure 2. Molecular mechanisms through which natural products regulate macrophage pyroptosis. Created using BioRender.com. ↑ indicates promotion and ⊥ indicates inhibition. PKM2, pyruvate kinase M2; SIRT1, Sirtuin 1; PLK1, polo-like kinase 1; DRP1, dynamin-related protein 1; ROS, reactive oxygen species; EP300, E1A binding protein p300; NLRP3, pyrin domain-containing protein 3; GSDMD, gasdermin D; EBP-δ, enhancer binding protein δ; GSDME, Gasdermin E.

Tangeretin attenuates acute lung injury in sepsis mice by modulating the PLK1/AMPK/DRP1 signaling axis by inhibiting ROS-mediated NLRP3 inflammasome activation and reducing pyroptosis of macrophages (87). Matrine inhibits NLRP3 inflammasome activation by modulating the protein tyrosine phosphatase non-receptor type 2/JNK/sterol regulatory element-binding protein 2 pathway, reduces macrophage pyroptosis and decreases the CLP-induced invasion of ALI- and LPS-stimulated macrophages in mice (88). Inhibition of STAT3 phosphorylation by colchicine inhibits the acetylation of the NLRP3 promoter by the STAT3/E1A binding protein p300 (EP300) complex, reducing pyroptosis and apoptosis in mouse alveolar macrophages, thereby attenuating sepsis-induced ALI (89). Verbenalin attenuates acute lung inflammation induced by pseudomonas aeruginosa by acting on the G protein-coupled receptor 18 receptor (90). Further studies found that verbenalin inhibits macrophage focal death and alleviates sepsis and IgG immune complex-induced ALI by inhibiting the C/enhancer binding protein δ (EBP-δ)/GSDMD/GSDME axis (91). Quercetin inhibits the nuclear accumulation of PKM2, upregulates SIRT1, inhibits the activation of NLRP3 inflammasomes and reduces the release of pyroptosis-related cytokines (IL-1β, IL-18 and HMGB1) in macrophages (92). Tiliroside targets the AMPK pathway, ameliorates mitochondrial damage, attenuates NLRP3 inflammasome activation, reduces pyroptosis in macrophages and ameliorates LPS-induced ALI in mice (93). Tabersonine is a natural NLRP3 inhibitor that inhibits inflammasome activation in macrophages and attenuates NLRP3-driven ALI in mice (94). Britannin specifically inhibits the NLRP3 inflammasome activation step in BMDMs and binds directly to the NLRP3 NACHT domain at Arg-335 and Gly271 (95). In addition, it inhibits NLRP3 activation in an ATPase-independent manner, inhibits the cleavage of caspase-1 and the secretion of mature IL-1β, and inhibits NLRP3-mediated pyroptosis in mouse and human macrophages (95). Taraxasterol inhibits NLRP3 inflammatory vesicle activation and pyroptosis in macrophages by modulating the mTOR signaling pathway, and is protective against LPS-induced BMDMs in mice (96). (+)-Syringaresinol activates PPARγ, thereby inhibiting the expression of NF-κB and C/EBP and reducing the inflammatory response (97). By targeting the NLRP3/GSDMD/caspase-1 axis, it suppressed macrophage pyroptosis and effectively alleviated IgG-IC-induced ALI (98). Alantolactone inhibits the activation and assembly of NLRP3 inflammasomes, LPS-ATP-induced IL-1β secretion and caspase-1 activation in macrophages by binding directly to the NACHT domain of NLRP; it also reduces macrophage pyroptosis (99). α-linolenic acid can alleviate NET-induced AM pyroptosis and ALI/ARDS by mediating pyrin inflammasome activation (100).

In conclusion, both flavonoids and terpenoids (except Verbenalin) inhibit macrophage autophagy through NLRP3 inflammasomes associated with cellular pyroptosis, and play a role in the treatment of ALI/ARDS.

Natural products that regulate macrophage phagocytosis

Macrophages are widely recognized as one of the main phagocytes that eliminate apoptotic cells (101). The exposed phosphatidylserine on the surface of apoptotic cells can be recognized and cleared by macrophages, which are subsequently activated to exert anti-inflammatory and immune responses (102,103). However, the HMGB1 protein binds to the receptor for advanced glycation end-products and αVβ3 on macrophages, and inhibits endocytosis (104). A study has shown that in patients with sepsis-associated ARDS, endocytosis by AMs is impaired, leading to the accumulation of apoptotic neutrophils, which can lead to long-term inflammation (105). Therefore, increasing endocytosis by macrophages can improve ALI/ARDS. Glucocorticoids upregulate endocytosis by macrophages through the type 1 isozyme of 3β-hydroxysteroid dehydrogenase (HSD-1), and HSD-1 deletion leads to impaired endocytosis by AMs, resulting in their inability to eliminate apoptotic neutrophils in model animals (106). AMs in the regression phase of ALI increased pinocytosis by upregulating integrin αv through vascular endothelial growth factor (VEGF)-C/VEGFR-3 signaling, thereby digesting the majority of exogenous apoptotic neutrophils and improving LPS-induced ALI (107). In addition, phagocytosis of apoptotic neutrophils by AMs is eliminated by reducing the expression of Gas6 following STAT6 (108). Macrophages have anti-inflammatory effects after engulfing human umbilical cord mesenchymal stem cell-derived apoptotic bodies (ABs). This is achieved by ABs expressing programmed death-ligand 1, which binds to PD1 on macrophages, affecting metabolic programming in macrophages and promoting their transition to an anti-inflammatory state (109). A Rab43 knockout study showed that the HMGB1 protein inhibits the phagocytosis of apoptotic cells by macrophages through inhibiting the transport of Rab43-controlled CD91 (a key receptor for macrophage pinocytosis) to the cell surface, which aggravates ALI/ARDS (110). Phagocytosis by macrophages is an important way to eliminate apoptotic neutrophils. This can reduce the release of harmful substances such as NETs, MPO and cytokines by neutrophils following, apoptosis and can effectively alleviate ALI/ARDS (111). The natural products that treat ALI/ARDS by regulating macrophage phagocytosis are summarized in Table III. An in vivo study has shown that chlorogenic acid significantly improves the lipopolysaccharide-induced inflammatory response and survival in CLP-induced ARDS mice by increasing phagocytosis by AMs (112). In addition, chlorogenic acid significantly upregulates the expression of GPR37 in vivo and in vitro. In addition, the protective effect of chlorogenic acid on ARDS was reversed after silencing GPR37 expression (112).

Table III. Natural products that regulate macrophage phagocytosis.

Natural products that regulate macrophage autophagy

Autophagy is a highly conserved protein degradation process involved in the degradation of protein cell components, such as lipoproteins and misfolded proteins (113). Cellular autophagy includes macroautophagy, microautophagy and chaperone-mediated autophagy (114). In general, autophagy has two functions, one of which is an early adaptive mechanism of the tissue, specifically the removal of organelles or proteins to maintain intracellular homeostasis (115). As an important component of innate immunity, macrophages play an important role in regulating the inflammatory response and the balance of the immune system (116). Autophagy also has an impact on ALI/ARDS. Studies have found that autophagy can regulate macrophage phagocytosis, antigen presentation and polarization. Furthermore, macrophage autophagy has a negative and positive role in the progression of ALI/ARDS (117). On the one hand, macrophage autophagy reduces the release of inflammatory cytokines and removes cellular debris, thereby attenuating lung injury and providing a protective effect (118). In a mouse model that lacked autophagy, excessive lung inflammation and injury occurred in the lungs of the mice, and treatment with an autophagy inducer activated the autophagy pathway in macrophages, resulting in a significant reduction in lung inflammation and injury (119). On the other hand, autophagy can exacerbate the damage and cause apoptosis, which can aggravate lung injury (117). Autoapoptosis, caused by increased autophagy of AMs, is one of the causes of LPS-induced lung injury in rats (120). The natural products that treat ALI/ARDS by regulating macrophage autophagy are summarized in Table IV. Sophoridine decreases the mRNA and protein expression of TLR4/myeloid differentiation primary response 88 (MyD88)/NF-κB and mTOR, enhances macrophage autophagy and reduces inflammation, thereby inhibiting LPS-induced ALI (121). Tetrahydropalmatine attenuates limb ischemia-reperfusion-induced ALI in rats by restoring autophagy mediated by the PI3K/AKT/mTOR pathway (122).

Table IV. Natural products that regulate macrophage autophagy.

In conclusion, alkaloids play a role in the prevention and treatment of ALI/ARDS by inhibiting the TLR4/MyD88/NF-κB and PI3K/AKT/mTOR signaling pathways and increasing macrophage autophagy.

Discussion

Macrophages play an important role in ALI/ARDS, and the regulation of macrophages may be an important means of intervention in ALI/ARDS (123). The present review summarizes and classifies the natural products that may be used for the treatment of ALI/ARDS discovered within the previous five years. These agents act by regulating macrophage abnormalities. Their main molecular mechanisms of action are summarized in Figs. 1 and 2. These products include flavonoids, alkaloids, terpenoids and quinones. The majority of these products work by regulating the polarization of macrophages. Their mechanisms of action include reducing M1 pro-inflammatory phenotype macrophages and increasing M2 anti-inflammatory phenotype macrophages to achieve anti-inflammatory effects. Metabolic programming is another factor that influences macrophage polarization, and interfering with macrophage metabolism also affects ALI/ARDS. M1 and M2 macrophages require different sources of energy for proliferation and cytokine production, with M1 macrophages highly dependent on aerobic glycolysis for energy, while M2 macrophages rely on mitochondrial oxidative phosphorylation and fatty acid oxidation for energy (124). Therefore, ALI can be prevented and treated by modulating metabolic programs to control macrophage polarization. Feng et al (125) found that M2-like immunophenotyping and metabolic reprogramming can be maintained by modulating high Ca2+ reactivity and long-term calcium signaling. Reprogramming glucose metabolism by activating the mTOR/HIF-1α/glycolytic pathway in macrophages activated by Trem-1 attenuates the inflammatory response in ALI (126,127). The inhibition of macrophage pyroptosis is also an important method for natural compounds to affect ALI/ARDS. In addition, some natural products also protect against alveolar damage by reducing macrophage autophagy and apoptosis, thereby protecting lung function and reducing pulmonary edema. Some natural products can alleviate ALI/ARDS by enhancing phagocytosis by macrophages.

In conclusion, different compounds may interfere with the development of ALI/ARDS by regulating polarization, pyroptosis, autophagy and phagocytosis of lung macrophages through the same or similar pathways or targets. Macrophage polarization often involves the NF-κB and AMPK pathways (Fig. 1), while pyroptosis mainly involves the NLRP3 inflammasome (Fig. 2). In addition, macrophage autophagy is associated with the TLR4/MyD88/NF-κB and PI3K/AKT/mTOR signaling pathways, whereas AM phagocytosis is associated with G-protein coupled receptor 37 enhancement (128). In addition, the main types of natural products that affect macrophage polarization are flavonoids, alkaloids, terpenoids and quinones, while the types of natural products that affect macrophage pyroptosis are flavonoids, alkaloids and terpenoids; at the same time, alkaloids can also increase macrophage autophagy. Notably, these natural products may all regulate both macrophage polarization and pyroptosis by affecting NF-κB, AMPK and NLRP3 inflammasomes. AMs are the first immune defenders against pathogens and foreign particles (129), accounting for ~95% of leukocytes in the lungs (130). AMs have a significant impact on the development of ALI after both infectious and non-infectious stimuli (10). Therefore, developing AM-specific drugs may be an important measure to target macrophages for the treatment of ALI/ARDS. However, most of the existing research results come from animal and cell experiments, and targeted therapy based on lung macrophages and macrophage-based treatment of ALI are still undergoing preclinical research. The clinical application of these findings remains a huge challenge.

At present, numerous studies of macrophages are systematic, and there are no further studies on the role of different types of macrophages in ALI/ARDS. However, lung macrophages are products of different macrophages, which may differ in function. Secondly, it has been reported that M1 and M2 phenotype changes may be associated with changes in different subgroups of cells during ARDS, and simply focusing on the M1 and M2 phenotypes cannot describe the multidimensional, complex and dynamic changes in macrophages in detail (9). The majority of current studies investigated the effect of macrophage polarization on ALI through cell labeling using molecules that were specific to the surface of M1 and M2 cells. Therefore, in the future, it is necessary to further explore the heterogeneity of macrophages with the help of advanced technologies such as single-cell RNA sequencing, assay for transposase-accessible chromatin with high throughput sequencing and mass spectrometry. This will improve the understanding of the role of different macrophages in the pathogenesis of ALI/ARDS, clarify the molecular mechanism of natural products that target and regulate macrophages during the treatment of ALI/ARDS, and provide new ideas and further research directions for the development of new drugs for the treatment of ALI/ARDS.

Acknowledgements

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Funding

This work was financially supported by the Yunnan Fundamental Research Projects (grant nos. 202201AU070167 and 202301AT070258), and the Yunnan Key Laboratory of Formulated Granules (grant no. 202105AG070014).

Availability of data and materials

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Authors' contributions

JL and WM conceived and designed the study; ZT, YL and RZ collected and organized data; YX wrote, reviewed and edited the manuscript; GL conceptualized and supervised the study, and performed project administration and funding acquisition. All authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

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Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

References