mTOR and autophagy in acute lung injury pathogenesis and therapeutic potential

Introduction

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are highly prevalent and potentially life-threatening pathological conditions that are characterized by the rapid onset of inflammation and damage to the alveolar epithelium and pulmonary endothelium. The high incidence rates of ALI and ARDS contribute to a significant proportion of mortalities. This increased mortality rate is primarily attributed to sepsis and the consequent development of multiple organ failure (1,2). In 2016, the diagnostic criteria for ALI were observed in 10% of patients admitted to intensive care units (ICUs); furthermore, 23% of patients receiving mechanical ventilation were diagnosed with ALI (1). Unfortunately, disturbingly high mortality rates of up to 31% were observed even among individuals who had prompt resolution of ALI (3,4). Common clinical manifestations of ALI include a sudden onset of dyspnea, severe hypoxemia, and bilateral pulmonary edema, characterized by the accumulation of fluid in the pulmonary airspaces. Pneumonia, non-pulmonary sepsis, and aspiration are frequently identified as triggers for ALI (1,4). It is noteworthy that the coronavirus disease 2019 (COVID-19) pandemic contributed significantly to a surge in ALI cases, especially in individuals with severe viral pneumonia that progressed to acute respiratory distress syndrome (1,4). Other emerging causes, such as the use of e-cigarettes or vaping products, have also been recognized (5).

ALI is characterized by substantial impairment of both the vascular endothelium and alveolar epithelium, resulting in compromised lung function and dysregulated pulmonary inflammation (4). Current clinical interventions for ALI mainly focus on mechanical ventilation and symptomatic management, owing to a lack of consistently effective pharmacological interventions (4). Therefore, further investigation into the underlying pathophysiological mechanisms is warranted to facilitate the development of novel therapeutic strategies.

The mammalian target of rapamycin (mTOR) is a critical protein involved in several important signaling pathways. It is specifically targeted by rapamycin, which is known for its immunosuppressive, antitumor, and neuroprotective properties (6). mTOR plays a crucial role in the regulation of autophagy, a cellular degradation process that is vital for maintaining cellular homeostasis (7). Autophagy is closely related to various pulmonary diseases, including ALI. Despite advances in understanding mTOR signaling, autophagy, and their roles in ALI, several critical gaps remain in the literature. Additionally, the precise molecular mechanisms through which mTOR modulates autophagy in ALI have not yet been fully elucidated. This review aims to provide a comprehensive understanding of the regulatory function of mTOR in autophagy and its intricate contribution to the progression of ALI, paving the way for novel therapeutic strategies.

The primary database utilized for this review was PubMed; it was selected because of its comprehensive coverage of biomedical literature and relevance to this topic. The key search terms were “mTOR”, “autophagy”, and “acute lung injury”. These terms were used individually and in combination to ensure a thorough exploration of the literature. Experimental studies, clinical trials, and review articles that focused on the role of mTOR and/or autophagy in the context of ALI and provided mechanistic insights or therapeutic implications were included. Studies that were not directly related to mTOR, autophagy, or ALI were excluded. A total of 59 studies were reviewed after applying the inclusion and exclusion criteria.

mTOR and its regulation of autophagy

mTOR, a member of the phosphoinositide 3-kinase (PI3K)-related protein kinase subfamily, is composed of two distinct complexes: mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 (8). mTORC1 consists of five subunits: mTOR, regulatory protein associated with mTOR (RAPTOR), mammalian lethal with Sec13 protein 8/G protein β-subunit-like protein (mLST8/GβL), proline-rich AKT substrate of 40 kDa (PRAS40), and DEPTOR [dishevelled, egl-10, and pleckstrin (DEP) domain-containing mTOR-interacting protein]. Conversely, mTORC2 comprises mTOR, DEPTOR, mLST8, rapamycin-insensitive companion of mTOR (RICTOR), mitogen-activated protein kinase-associated protein 1 (mSin1), and protein observed with rictor-1 and 2 (PROTOR1/2) (8).

mTOR is responsive to numerous environmental cues, including low energy conditions or growth factor signals, and regulates cellular growth, metabolism, and survival through downstream signaling pathways (6). The tuberous sclerosis complex 1/2 (TSC1/2) is the central upstream regulator of mTORC1. The complex functions as a guanosine triphosphatase (GTPase)-activating protein (GAP) for the small GTPase, Ras homolog enriched in brain (Rheb). Inhibition of the TSC complex allows Rheb to remain in its active GTP-bound state, which directly activates mTORC1 (8).

The binding of growth factors, such as insulin, to their receptors leads to the activation of PI3K, which generates phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 activates protein kinase B (AKT), which in turn phosphorylates and inhibits TSC1/2, then activates Rheb, which stimulates mTORC1 (8). Similar to the PI3K/AKT pathway, growth factors could activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, also known as the Ras-Raf-MEK-ERK pathway. This pathway can lead to the activation of ERK. ERK can phosphorylate TSC2 at different sites than AKT, which can also inhibit the TSC1/2 complex, thereby promoting mTORC1 activation (8). Moreover, amino acids, especially leucine and arginine, activate mTORC1 through the Rag GTPases, and recruit mTORC1 to the lysosomal surface, where it interacts with Rheb (8).

In instances of energy stress, the serine/threonine kinase LKB1 activates the adenosine 5’-monophosphate-activated protein kinase (AMPK) in response to low energy levels. AMPK phosphorylates and activates TSC2, enhancing its ability to inhibit mTORC1 (8). Under hypoxic conditions, regulated in development and DNA damage responses 1 (REDD1) is upregulated. REDD1 activates the TSC1/2 complex, leading to the inhibition of mTORC1 to conserve resources under low oxygen conditions (8). Under DNA damage and other cellular stress, p53 becomes activated, leading to expression of TSC2, thus, negatively regulating mTORC1 (8).

mTOR is a well-known negative regulator of autophagy (Figure 1). The activation of the uncoordinated-51-like protein kinase (ULK1) is an early step in autophagy, forming a complex with autophagy-related gene (ATG)13, ATG101, and focal adhesion kinase family-interacting protein (FIP200). mTORC1 phosphorylates ULK1, thereby blocking the initiation of autophagosome formation and negatively regulating the process of autophagy (8,9). Additionally, mTORC1 phosphorylates and inhibits the transcription factor EB (TFEB) family members, which are essential for the expression of several autophagy-related proteins and lysosomal factors (8,10). Similar to mTORC1, mTORC2 has also been shown to act as a negative regulator of autophagy. Several key molecular players involved in autophagy-related pathways have been directly associated with the activity of mTORC2 (11).

Figure 1 Schemata about the roles of mTOR and autophagy in ALI. Key upstream signals regulate autophagy through mTORC1 in the context of ALI. On the left, alveolar damage, immune cell infiltration, and increased permeability demonstrate how bacteria, viruses, or hypoxia trigger inflammation and further tissue damage. On the right, signals such as REDD1, PI3K/AKT, MAPK/ERK, AMPK, and p53 influence TSC1/2 and Rheb to control mTORC1 activity. When mTORC1 is active, autophagy is inhibited by preventing the activation of ULK1 complex and TFEB. AKT, protein kinase B; ALI, acute lung injury; AMPK, adenosine 5’-monophosphate-activated protein kinase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; PI3K, phosphoinositide 3-kinase; REDD1, regulated in development and DNA damage responses 1; Rheb, Ras homolog enriched in brain; TFEB, transcription factor EB; TSC1/2, tuberous sclerosis complex 1/2; ULK1, uncoordinated-51-like protein kinase.

Role of autophagy in ALI

Autophagy is a highly conserved cellular degradation and recycling process that can be morphologically classified into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy (12). All three types involve the proteolytic degradation of cytosolic components at the lysosome through the action of lysosomal acid proteases. Serving as a cellular housekeeping process, autophagy not only eliminates protein aggregates, damaged organelles, and intracellular pathogens but also recycles the degradation products for reuse within cells. Dysregulation of autophagy has also been implicated in non-apoptotic cell death processes (13).

A growing body of evidence indicates that autophagy plays a vital role in maintaining cellular homeostasis and is involved in the pathogenesis of various diseases, particularly neurodegenerative conditions, inflammatory disorders, and cancer. Autophagic processes are controlled by a set of ATGs that are essential for the proper formation of autophagosomes (14). Notably, Beclin-1/ATG6 was the first mammalian autophagy-related gene identified and is known to play a significant role in the formation of the autophagosome as well as the maturation of autophagosomes and endosomes (15). Another critical protein in autophagy is microtubule-associated protein 1 light chain 3 (LC3), particularly its isoform LC3B, an autophagosomal ortholog of yeast ATG8. LC3B is lipidated with phosphatidylethanolamine, forming LC3-II, which serves as a reliable marker for autophagosomes in mammalian cells (16,17). These two proteins are commonly used as markers in autophagy research.

Autophagy has been observed to have both protective and detrimental effects on the pathogenesis and progression of ALI (18-20). On the one hand, autophagy can limit excessive inflammatory responses by degrading pro-inflammatory mediators and damaged mitochondria. By removing damaged organelles and proteins, autophagy promotes the survival and function of cells. On the other hand, overactive autophagy leads to excessive degradation of cellular components, contributing to cell death and worsening lung injury. The study has reported different levels of autophagy in different stages of lipopolysaccharide (LPS)-induced ALI, suggesting its involvement in the disease (21).

mTOR and autophagy in ALI

mTOR and autophagy are key regulators of the pathogenesis and resolution of ALI (Figure 1). Excessive mTOR activity can exacerbate inflammation and tissue damage, while insufficient mTOR activity can impair cell survival and tissue repair. Meanwhile, proper regulation of autophagy is essential for mitigating lung injury and promoting recovery. Their interplay determines the balance between inflammation, cell survival, and tissue repair, making them critical targets for therapeutic intervention. The roles of mTOR and autophagy have been found to vary among different cell types and different models. Several animal models of ALI have been utilized, and were induced by stimuli such as LPS, ischemia/reperfusion (I/R) injury, and cecal ligation and puncture (CLP).

Figure 1 shows how ALI develops and the upstream signals that control autophagy through mTORC1. On the left, alveolar and vascular structures face damage from pathogens or hypoxia. Injured epithelial and endothelial cells release cytokines, drawing immune cells into the lung. These cells produce more mediators, raising permeability and cell death. On the right, pathways such as PI3K/AKT, MAPK/ERK, AMPK, and p53 act on TSC1/2 and Rheb to regulate mTORC1. When active, mTORC1 inhibits ULK1 complex and TFEB, blocking autophagy. Under stress or limited nutrients, mTORC1 activity drops, allowing autophagy to proceed. Amino acids (e.g., leucine, arginine) also modulate mTORC1 through Rag GTPases, positioning it at the lysosome where Rheb refines autophagy control. In this context, we will discuss the specific roles of autophagy in various cell types, with an emphasis on the involvement of the mTOR pathway.

Epithelial cells

The intact alveolar epithelium functions as a robust defense against alveolar flooding. Disruption of epithelial cells, such as apoptosis or necrosis, as well as disruption of intercellular junctions, can impair fluid transport and increase epithelial barrier permeability (4).

Autophagy has been implicated in the pathogenesis of ALI, particularly in lung epithelial cells. However, as summarized in Table 1, the specific impact of autophagy varies across different models. In nanoparticle-induced ALI, deregulation of the AKT-TSC2-mTOR signaling pathway triggers autophagic cell death. Inhibition of autophagy with 3-methyladenine (3-MA) has been shown to reduce epithelial cell death and ameliorate ALI (22). Similarly, in hemagglutinin type 5 and neuraminidase type 1 (H5N1) influenza virus infection, autophagic cell death in lung epithelial cells is driven by mTOR suppression or AKT-TSC pathway activation. Blocking autophagy via Beclin-1 knockdown or 3-MA reduces epithelial cell loss and improves outcomes (23,24).

Additional investigations further reinforce the notion that autophagy inhibition can be protective. For instance, hydrogen sulfide (H2S) ameliorates lung damage by mitigating autophagy (25,26), through the PI3K/AKT/mTOR pathway (26). Xenogeneic and allogeneic mesenchymal stem cells could protect the lung against I/R injury, partly through the downregulation of autophagy in rats (27). MicroRNA-34a suppresses excessive autophagic activity in alveolar type II epithelial cells (AECII) to reduce cellular damage in LPS-induced ALI (28). Hyperoxia has been shown to induce lung injury by enhancing AECII autophagy via activation of the mTOR pathway (29). Liensinine was reported to alleviate LPS-induced ALI by blocking autophagic flux via PI3K/AKT/mTOR signaling pathway (30). Furthermore, advanced glycation end-product receptor inhibition alleviated LPS-induced lung injury by directly suppressing autophagic apoptosis of alveolar epithelial cells (31).

Conversely, other studies indicate that autophagy activation may be beneficial. Rapamycin, the mTOR inhibitor, has been shown to activate autophagy, limit the proinflammatory response, and downregulate apoptotic activity in CLP-induced ALI (32). Whereas, in LPS-induced ALI, the activation of mTOR suppresses autophagy, thereby contributing to inflammatory responses in the epithelium, while rapamycin effectively alleviates lung injury (33). Upon exposure to hyperoxia, activating autophagy through the inhibition of the regulatory-associated protein of mTOR demonstrates a protective role with an antiapoptotic response (34). Additionally, cinobufagin, a primary component isolated from cinobufotalin, was proven to enhance autophagy through the p53/mTOR pathway in LPS-induced ALI (35). Other studies have demonstrated that targeting mTOR to induce autophagy could ameliorate LPS-induced ALI (36-39).

In line with this protective role, silencing LC3B augments hyperoxia-induced cell death in epithelial cells, whereas LC3B overexpression confers protection (40). The gene WWOX, linked to lung diseases, helps reduce LPS-induced lung injury by activating autophagy through mTOR (41). Overall, these studies provide valuable insights into the intricate association between autophagy and lung epithelial cells in the pathogenesis of ALI. Modulating autophagy by targeting the mTOR pathway holds significant promise as a potential therapeutic approach for ALI. However, further comprehensive investigations are necessary to fully elucidate the intricate molecular mechanisms underlying this relationship.

Endothelial cells

The pulmonary vascular endothelium serves a dual role as both a physical barrier and an active regulator of various physiological processes, including vessel permeability, signaling, and angiogenesis (42). Disruption of the vascular endothelial cells can lead to an increase in capillary permeability, contributing significantly to the development of ALI (42).

Table 2 primarily summarizes the literature on the role of autophagy in endothelial cells during ALI. Some reports show that blocking or reducing autophagy can protect the endothelium. One study found that 3-MA lowers lung leakage and swelling, which helps repair the endothelial barrier (43). Astragaloside IV also decreases autophagy, raises cell survival, strengthens tight junctions, and reduces cell death (44). In another study, blocking autophagy by using 3-MA or ATG5 small interfering RNA (siRNA) cut endothelial permeability (45). Autophagy has been extensively studied in the context of endothelial cell inflammation and vascular permeability. Silencing the Beclin1 gene has been shown to restore endothelial cell barrier integrity (46). In hemorrhagic shock-induced ALI, autophagy was increased in lung tissue and contributed to lung problems (47). Similarly, research also indicates that autophagy mediates I/R injury in endothelial cells (48).

Other studies show that raising autophagy can be beneficial. Hydrogen-rich saline, for example, triggered autophagy in LPS-induced ALI and downregulated the mTOR/TFEB pathway, which reduced lung injury and endothelial dysfunction (49). Additional reports noted that stopping autophagy made LPS-induced ALI worse (50,51). Apelin-13 lowers lung damage and vascular leakage by increasing autophagic flux (52). Small extracellular vesicles derived from adipose-derived stem cells effectively alleviated LPS-induced endothelial cell barrier damage and lung injury, while autophagy inhibition markedly weakened the therapeutic effect (53). Hyperoside also reduces endothelial damage through ATG13-mediated autophagy, though stopping this pathway cancels its protective role (54). Transplantation of mesenchymal stem cells was proven to significantly reduce the severity of LPS-induced ALI in mice by increasing autophagy in endothelial cells to promote their survival (55). Additionally, sevoflurane has been shown to suppress apoptosis and inflammation by activating protective autophagy (56). Adipose-derived stem cells significantly alleviated LPS-induced microvascular barrier injury, and inhibiting autophagy weakened paracrine functions and protective effects (57). Additionally, estrogen-related receptor alpha was demonstrated to protect against sepsis-induced ALI through the regulation of the balance between autophagy and apoptosis; the promotion of its expression enhanced autophagy and reduced CLP-induced ALI (58). Plasma extracellular vesicles carrying microRNA-210-3p block autophagy through ATG7, which increases inflammation in CLP-induced ALI (59). Integrin αvβ5 inhibition was found to protect against I/R-induced lung injury by promoting autophagy, thus alleviating cell permeability and decreasing the apoptosis ratio (60). In another research, autophagy has also been shown to have a protective effect as it attenuates endothelial cell damage and mitigates cell death (61).

Overall, the impact of autophagy on endothelial cells in ALI is not straightforward. Some studies show that reducing autophagy helps maintain barrier function, while others indicate that promoting autophagy is crucial for cell survival and repair. These findings point to a complicated balance: autophagy can both protect and damage the endothelium under different conditions. More work is needed to understand how best to regulate autophagy to treat ALI.

Macrophages

Macrophages play a crucial role in initiating and maintaining the pulmonary immune response and homeostasis (62). Macrophages are recruited to the lungs in the presence of infection or injury, and this can exacerbate the inflammatory process (62). Macrophage autophagy primarily reduces pulmonary inflammation and lung injury, although it can worsen lung injury in some animal models (62).

Table 3 provides a comprehensive overview of studies investigating the impact of autophagy on macrophages in ALI. Many studies link increased macrophage autophagy with better outcomes in ALI. One report found that GYY4137, a novel H2S donor, blocks mTOR signaling, raises autophagy, and lessens lung injury (63). Another showed that glycyrrhizic acid lowers LPS-induced injury through the PI3K/AKT/mTOR pathway, and 3-MA can reverse this benefit (64). A separate investigation indicates that a cobalquinone B derivative triggers autophagy in alveolar macrophages by blocking AKT-mTOR, improving bacterial clearance and limiting lung damage in a Pseudomonas aeruginosa model (65). In acute radiation pneumonitis, hydrogen-rich saline stops polarization and reduces oxidative stress, then activates autophagy via AMPK/mTOR/ULK1 (66). Meanwhile, irisin repairs autophagy flux through AMPK/mTOR, lowering particulate matter 2.5 (PM2.5)-induced lung injury (67). Moreover, BML-111 (a lipoxin A4 receptor agonist) (68) and early-stage autophagy activation (69) both lower alveolar macrophage apoptosis. Strengthening autophagy can additionally suppress the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, thereby limiting interleukin (IL)-1β and IL-18 release (70-73).

Despite these benefits, other studies show that macrophage autophagy can contribute to lung damage. Complement C5a promotes alveolar macrophage apoptosis through an autophagy-related pathway, disrupting pulmonary homeostasis (74). Another study indicates that macrophage autophagy boosts inflammation (75). In LPS-induced models, resveratrol (a strong SIRT-1 activator) reduces cell death by blocking autophagy, though rapamycin nullifies this benefit (76). Hydrogen-rich saline also shields the lungs during sepsis by lowering autophagy, adjusting macrophage polarization, and reducing apoptosis (77).

Taken together, these findings highlight the dual role of macrophage autophagy in ALI. In many scenarios, activating autophagy in macrophages limits inflammation and promotes tissue repair. Yet, under different conditions, heightened autophagy can worsen lung damage by increasing apoptosis and inflammation. Recognizing these context-dependent outcomes is essential for developing effective treatments that target macrophage autophagy in ALI.

Neutrophils

The accumulation of white blood cells, particularly neutrophils, in the lung and alveolar space is clinically and pathologically significant in ALI (4). This process involves the migration of activated neutrophils into the lung to combat inflammation and infection. However, excessive accumulation of neutrophils can lead to tissue damage and worsen lung injury.

Researches about the impact of autophagy on neutrophils in ALI are shown in Table 4. Several reports indicate that promoting autophagy in neutrophils reduces their damaging effects. In models with impaired autophagic flux, higher neutrophil extracellular traps (NETs) formation heightens inflammation (78). NETs are web-like structures that are released by activated neutrophils to trap and kill pathogens. By contrast, interventions that restore autophagy lower NET release and help contain the inflammatory response. Rapamycin also lowers polymorphonuclear neutrophil counts and cytokine levels in CLP-induced ALI, hinting at a protective role for autophagy; conversely, inhibiting autophagy with 3-MA worsens these markers (79). Programmed death ligand 1 (PD-L1) also maintains the release of NETs by regulating autophagy via PI3K/AKT/mTOR pathway in ARDS (80). Meanwhile, mTORC1 drives neutrophil activation in response to Toll-like receptor (TLR)2/4 stimulation, and rapamycin-mediated mTORC1 inhibition lowers cytokine release and lung damage (81).

Another study shows that inhibition of autophagy in neutrophils reduces degranulation and alleviates LPS-induced ALI (82). Thus, although neutrophil accumulation is crucial for infection control, misregulated autophagy or mTORC1 activity can turn a protective immune response into one that harms lung tissue.

Generally, the dysregulation of neutrophil function, impairment of autophagy, and mTORC1 activation contribute to the development and worsening of ALI. Understanding the intricate interplay between neutrophil activation, autophagy, and mTORC1 signaling holds promise for the development of novel therapeutic strategies for ALI.

Discussion

Current studies suggest that autophagy plays a complex and context-dependent role in ALI, offering potential therapeutic targets. Balancing autophagy activation and inhibition, depending on the stage and severity of the lung injury, could improve the outcomes of patients with ALI. Targeting the mTOR pathway to modulate autophagy may enhance the clearance of damaged cellular components, reduce inflammation, and promote tissue repair, thereby ameliorating the severity of ALI. This therapeutic approach holds potential due to its ability to address the underlying cellular dysfunctions associated with ALI, offering a novel avenue for treatment.

It is worth noting that DEPTOR is a natural inhibitor of mTOR (83). The role of DEPTORs in inhibiting mTOR activity makes it an intriguing emerging target for the treatment of ALI. The specificity of DEPTOR in inhibiting mTOR, along with its natural presence in the body, suggests that therapies based on DEPTOR modulation could offer a more nuanced and potentially safer alternative to broad-spectrum mTOR inhibitors, such as rapamycin. Recent research has highlighted DEPTOR’s potential in modulating the mTOR pathway to achieve therapeutic benefits in various diseases, including cancer and metabolic disorders. However, its role in ALI is still under investigation. By increasing DEPTOR levels or mimicking its inhibitory effects on mTOR, it may be possible to develop new therapeutic strategies that specifically target the pathological processes underlying ALI. Further research is needed to fully understand the regulatory mechanisms of DEPTOR in lung tissues and its impact on the complex pathophysiology of ALI.

Although our review comprehensively examined the role of mTOR and autophagy in ALI, it has some limitations. This review’s reliance on published literature may be subject to publication bias, favoring studies with positive results. Additionally, the heterogeneity of the studies reviewed, including differences in experimental models and methodologies, poses a challenge in drawing unified conclusions. Furthermore, the rapidly evolving nature of research in this field suggests that more recent studies may have been published since the literature search for this review was conducted, potentially affecting the relevance and applicability of the review’s findings.

Conclusions

Future treatment strategies for the management of ALI could involve a combination of mTOR inhibitors and autophagy modulators, tailored to the patient’s specific pathophysiological condition. Furthermore, understanding the precise molecular mechanisms governing mTOR and autophagy in ALI could lead to the development of more targeted therapies, minimizing potential side effects and maximizing therapeutic efficacy. The continued exploration of these pathways in ALI research holds significant potential for advancing treatment options and improving patient outcomes.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1817/prf

Funding: This work was supported in part by the Technology Project of Zhejiang Provincial Health Commission (No. 2022482758, to Y.H.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1817/coif). Y.H. receives funding from the Technology Project of Zhejiang Provincial Health Commission (No. 2022482758). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bellani G, Laffey JG, Pham T, et al. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA 2016;315:788-800. [Crossref] [PubMed]
2. Stapleton RD, Wang BM, Hudson LD, et al. Causes and timing of death in patients with ARDS. Chest 2005;128:525-32. [Crossref] [PubMed]
3. Madotto F, Pham T, Bellani G, et al. Resolved versus confirmed ARDS after 24 h: insights from the LUNG SAFE study. Intensive Care Med 2018;44:564-77. [Crossref] [PubMed]
4. Meyer NJ, Gattinoni L, Calfee CS. Acute respiratory distress syndrome. Lancet 2021;398:622-37. [Crossref] [PubMed]
5. Park JA, Crotty Alexander LE, Christiani DC. Vaping and Lung Inflammation and Injury. Annu Rev Physiol 2022;84:611-29. [Crossref] [PubMed]
6. Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol 2020;21:183-203. [Crossref] [PubMed]
7. Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 2015;125:25-32. [Crossref] [PubMed]
8. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell 2017;168:960-76. [Crossref] [PubMed]
9. Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009;20:1992-2003. [Crossref] [PubMed]
10. Deleyto-Seldas N, Efeyan A. The mTOR-Autophagy Axis and the Control of Metabolism. Front Cell Dev Biol 2021;9:655731. [Crossref] [PubMed]
11. Ballesteros-Álvarez J, Andersen JK. mTORC2: The other mTOR in autophagy regulation. Aging Cell 2021;20:e13431. [Crossref] [PubMed]
12. Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 2014;20:460-73. [Crossref] [PubMed]
13. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol 2010;221:3-12. [Crossref] [PubMed]
14. Levine B, Kroemer G. Biological Functions of Autophagy Genes: A Disease Perspective. Cell 2019;176:11-42. [Crossref] [PubMed]
15. Xu HD, Qin ZH. Beclin 1, Bcl-2 and Autophagy. Adv Exp Med Biol 2019;1206:109-26. [Crossref] [PubMed]
16. Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 2004;36:2503-18. [Crossref] [PubMed]
17. Vishnupriya S, Priya Dharshini LC, Sakthivel KM, et al. Autophagy markers as mediators of lung injury-implication for therapeutic intervention. Life Sci 2020;260:118308. [Crossref] [PubMed]
18. Aggarwal S, Mannam P, Zhang J. Differential regulation of autophagy and mitophagy in pulmonary diseases. Am J Physiol Lung Cell Mol Physiol 2016;311:L433-52. [Crossref] [PubMed]
19. Li ZY, Wu YF, Xu XC, et al. Autophagy as a double-edged sword in pulmonary epithelial injury: a review and perspective. Am J Physiol Lung Cell Mol Physiol 2017;313:L207-17. [Crossref] [PubMed]
20. Liao SX, Sun PP, Gu YH, et al. Autophagy and pulmonary disease. Ther Adv Respir Dis 2019;13:1753466619890538. [Crossref] [PubMed]
21. Lin L, Zhang L, Yu L, et al. Time-dependent changes of autophagy and apoptosis in lipopolysaccharide-induced rat acute lung injury. Iran J Basic Med Sci 2016;19:632-7. [PubMed]
22. Li C, Liu H, Sun Y, et al. PAMAM nanoparticles promote acute lung injury by inducing autophagic cell death through the Akt-TSC2-mTOR signaling pathway. J Mol Cell Biol 2009;1:37-45. [Crossref] [PubMed]
23. Ma J, Sun Q, Mi R, et al. Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling. J Genet Genomics 2011;38:533-7. [Crossref] [PubMed]
24. Sun Y, Li C, Shu Y, et al. Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection. Sci Signal 2012;5:ra16. [Crossref] [PubMed]
25. Ge X, Sun J, Fei A, et al. Hydrogen sulfide treatment alleviated ventilator-induced lung injury through regulation of autophagy and endoplasmic reticulum stress. Int J Biol Sci 2019;15:2872-84. [Crossref] [PubMed]
26. Xu X, Li H, Gong Y, et al. Hydrogen sulfide ameliorated lipopolysaccharide-induced acute lung injury by inhibiting autophagy through PI3K/Akt/mTOR pathway in mice. Biochem Biophys Res Commun 2018;507:514-8. [Crossref] [PubMed]
27. Lin KC, Yeh JN, Chen YL, et al. Xenogeneic and Allogeneic Mesenchymal Stem Cells Effectively Protect the Lung Against Ischemia-reperfusion Injury Through Downregulating the Inflammatory, Oxidative Stress, and Autophagic Signaling Pathways in Rat. Cell Transplant 2020;29:963689720954140. [Crossref] [PubMed]
28. Song L, Zhou F, Cheng L, et al. MicroRNA-34a Suppresses Autophagy in Alveolar Type II Epithelial Cells in Acute Lung Injury by Inhibiting FoxO3 Expression. Inflammation 2017;40:927-36. [Crossref] [PubMed]
29. Ren Y, Qin S, Liu X, et al. Hyperoxia can Induce Lung Injury by Upregulating AECII Autophagy and Apoptosis Via the mTOR Pathway. Mol Biotechnol 2024;66:3357-68. [Crossref] [PubMed]
30. Wang C, Zou K, Diao Y, et al. Liensinine alleviates LPS-induced acute lung injury by blocking autophagic flux via PI3K/AKT/mTOR signaling pathway. Biomed Pharmacother 2023;168:115813. [Crossref] [PubMed]
31. Xiong X, Dou J, Shi J, et al. RAGE inhibition alleviates lipopolysaccharides-induced lung injury via directly suppressing autophagic apoptosis of type II alveolar epithelial cells. Respir Res 2023;24:24. [Crossref] [PubMed]
32. Yen YT, Yang HR, Lo HC, et al. Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury. Surgery 2013;153:689-98. [Crossref] [PubMed]
33. Hu Y, Lou J, Mao YY, et al. Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury. Autophagy 2016;12:2286-99. [Crossref] [PubMed]
34. Sureshbabu A, Syed M, Das P, et al. Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice. Am J Respir Cell Mol Biol 2016;55:722-35. [Crossref] [PubMed]
35. Wang C, Mei X, Wu Y, et al. Cinobufagin alleviates lipopolysaccharide-induced acute lung injury by regulating autophagy through activation of the p53/mTOR pathway. Front Pharmacol 2022;13:994625. [Crossref] [PubMed]
36. Zeng M, Sang W, Chen S, et al. 4-PBA inhibits LPS-induced inflammation through regulating ER stress and autophagy in acute lung injury models. Toxicol Lett 2017;271:26-37. [Crossref] [PubMed]
37. Wei X, Yi X, Lv H, et al. MicroRNA-377-3p released by mesenchymal stem cell exosomes ameliorates lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy. Cell Death Dis 2020;11:657. [Crossref] [PubMed]
38. Yang B, Ma L, Wei Y, et al. Isorhamnetin alleviates lipopolysaccharide-induced acute lung injury by inhibiting mTOR signaling pathway. Immunopharmacol Immunotoxicol 2022;44:387-99. [Crossref] [PubMed]
39. Cao J, Mai H, Chen Y, et al. Ketamine Promotes LPS-Induced Pulmonary Autophagy and Reduces Apoptosis through the AMPK/mTOR Pathway. Contrast Media Mol Imaging 2022;2022:8713701. [Crossref] [PubMed]
40. Tanaka A, Jin Y, Lee SJ, et al. Hyperoxia-induced LC3B interacts with the Fas apoptotic pathway in epithelial cell death. Am J Respir Cell Mol Biol 2012;46:507-14. [Crossref] [PubMed]
41. Wang C, Yang Y, Zhou C, et al. WWOX activates autophagy to alleviate lipopolysaccharide-induced acute lung injury by regulating mTOR. Int Immunopharmacol 2023;115:109671. [Crossref] [PubMed]
42. Nova Z, Skovierova H, Calkovska A. Alveolar-Capillary Membrane-Related Pulmonary Cells as a Target in Endotoxin-Induced Acute Lung Injury. Int J Mol Sci 2019;20:831. [Crossref] [PubMed]
43. Slavin SA, Leonard A, Grose V, et al. Autophagy inhibitor 3-methyladenine protects against endothelial cell barrier dysfunction in acute lung injury. Am J Physiol Lung Cell Mol Physiol 2018;314:L388-96. [Crossref] [PubMed]
44. Liu B, Zhao H, Wang Y, et al. Astragaloside IV Attenuates Lipopolysaccharides-Induced Pulmonary Epithelial Cell Injury through Inhibiting Autophagy. Pharmacology 2020;105:90-101. [Crossref] [PubMed]
45. Zhao Y, Zhang H, Zhang SL, et al. Upregulation of FOXO1 contributes to lipopolysaccharide-induced pulmonary endothelial injury by induction of autophagy. Ann Transl Med 2022;10:630. [Crossref] [PubMed]
46. Leonard A, Millar MW, Slavin SA, et al. Critical role of autophagy regulator Beclin1 in endothelial cell inflammation and barrier disruption. Cell Signal 2019;61:120-9. [Crossref] [PubMed]
47. Sun Q, Zhang H, Du HB, et al. ESTROGEN ALLEVIATES POSTHEMORRHAGIC SHOCK MESENTERIC LYMPH-MEDIATED LUNG INJURY THROUGH AUTOPHAGY INHIBITION. Shock 2023;59:754-62. [PubMed]
48. Xie X, Zhu T, Chen L, et al. MCPIP1-induced autophagy mediates ischemia/reperfusion injury in endothelial cells via HMGB1 and CaSR. Sci Rep 2018;8:1735. [Crossref] [PubMed]
49. Fu Z, Zhang Z, Wu X, et al. Hydrogen-Rich Saline Inhibits Lipopolysaccharide-Induced Acute Lung Injury and Endothelial Dysfunction by Regulating Autophagy through mTOR/TFEB Signaling Pathway. Biomed Res Int 2020;2020:9121894. [Crossref] [PubMed]
50. Zhang D, Zhou J, Ye LC, et al. Autophagy maintains the integrity of endothelial barrier in LPS-induced lung injury. J Cell Physiol 2018;233:688-98. [Crossref] [PubMed]
51. Dong W, He B, Qian H, et al. RAB26-dependent autophagy protects adherens junctional integrity in acute lung injury. Autophagy 2018;14:1677-92. [Crossref] [PubMed]
52. Kong X, Lin D, Lu L, et al. Apelin-13-Mediated AMPK ameliorates endothelial barrier dysfunction in acute lung injury mice via improvement of mitochondrial function and autophagy. Int Immunopharmacol 2021;101:108230. [Crossref] [PubMed]
53. Li C, Wang M, Wang W, et al. Autophagy regulates the effects of ADSC-derived small extracellular vesicles on acute lung injury. Respir Res 2022;23:151. [Crossref] [PubMed]
54. Mai J, He Q, Liu Y, et al. Hyperoside Attenuates Sepsis-Induced Acute Lung Injury (ALI) through Autophagy Regulation and Inflammation Suppression. Mediators Inflamm 2023;2023:1257615. [Crossref] [PubMed]
55. Zhou Z, You Z. Mesenchymal Stem Cells Alleviate LPS-Induced Acute Lung Injury in Mice by MiR-142a-5p-Controlled Pulmonary Endothelial Cell Autophagy. Cell Physiol Biochem 2016;38:258-66. [Crossref] [PubMed]
56. Fu Z, Wu X, Zheng F, et al. Activation of the AMPK-ULK1 pathway mediated protective autophagy by sevoflurane anesthesia restrains LPS-induced acute lung injury (ALI). Int Immunopharmacol 2022;108:108869. [Crossref] [PubMed]
57. Li C, Pan J, Ye L, et al. Autophagy regulates the therapeutic potential of adipose-derived stem cells in LPS-induced pulmonary microvascular barrier damage. Cell Death Dis 2019;10:804. [Crossref] [PubMed]
58. Xia W, Pan Z, Zhang H, et al. ERRα protects against sepsis-induced acute lung injury in rats. Mol Med 2023;29:76. [Crossref] [PubMed]
59. Li G, Wang B, Ding X, et al. Plasma extracellular vesicle delivery of miR-210-3p by targeting ATG7 to promote sepsis-induced acute lung injury by regulating autophagy and activating inflammation. Exp Mol Med 2021;53:1180-91. [Crossref] [PubMed]
60. Zhang D, Li C, Song Y, et al. Integrin αvβ5 inhibition protects against ischemia-reperfusion-induced lung injury in an autophagy-dependent manner. Am J Physiol Lung Cell Mol Physiol 2017;313:L384-94. [Crossref] [PubMed]
61. Zhang D, Li C, Zhou J, et al. Autophagy protects against ischemia/reperfusion-induced lung injury through alleviating blood-air barrier damage. J Heart Lung Transplant 2015;34:746-55. [Crossref] [PubMed]
62. Liu C, Xiao K, Xie L. Progress in preclinical studies of macrophage autophagy in the regulation of ALI/ARDS. Front Immunol 2022;13:922702. [Crossref] [PubMed]
63. Li J, Li M, Li L, et al. Hydrogen sulfide attenuates ferroptosis and stimulates autophagy by blocking mTOR signaling in sepsis-induced acute lung injury. Mol Immunol 2022;141:318-27. [Crossref] [PubMed]
64. Qu L, Chen C, He W, et al. Glycyrrhizic acid ameliorates LPS-induced acute lung injury by regulating autophagy through the PI3K/AKT/mTOR pathway. Am J Transl Res 2019;11:2042-55. [PubMed]
65. Zhu P, Bu H, Tan S, et al. A Novel Cochlioquinone Derivative, CoB1, Regulates Autophagy in Pseudomonas aeruginosa Infection through the PAK1/Akt1/mTOR Signaling Pathway. J Immunol 2020;205:1293-305. [Crossref] [PubMed]
66. Yin Z, Xu W, Ling J, et al. Hydrogen-rich solution alleviates acute radiation pneumonitis by regulating oxidative stress and macrophages polarization. J Radiat Res 2024;65:291-302. [Crossref] [PubMed]
67. Ma J, Han Z, Jiao R, et al. Irisin Ameliorates PM2.5-Induced Acute Lung Injury by Regulation of Autophagy Through AMPK/mTOR Pathway. J Inflamm Res 2023;16:1045-57. [Crossref] [PubMed]
68. Liu H, Zhou K, Liao L, et al. Lipoxin A4 receptor agonist BML-111 induces autophagy in alveolar macrophages and protects from acute lung injury by activating MAPK signaling. Respir Res 2018;19:243. [Crossref] [PubMed]
69. Fan T, Chen L, Huang Z, et al. Autophagy decreases alveolar macrophage apoptosis by attenuating endoplasmic reticulum stress and oxidative stress. Oncotarget 2016;7:87206-18. [Crossref] [PubMed]
70. Jia X, Cao B, An Y, et al. Rapamycin ameliorates lipopolysaccharide-induced acute lung injury by inhibiting IL-1β and IL-18 production. Int Immunopharmacol 2019;67:211-9. [Crossref] [PubMed]
71. Peng W, Peng F, Lou Y, et al. Autophagy alleviates mitochondrial DAMP-induced acute lung injury by inhibiting NLRP3 inflammasome. Life Sci 2021;265:118833. [Crossref] [PubMed]
72. Li D, Li C, Wang T, et al. Geranylgeranyl diphosphate synthase 1 knockdown suppresses NLRP3 inflammasome activity via promoting autophagy in sepsis-induced acute lung injury. Int Immunopharmacol 2021;100:108106. [Crossref] [PubMed]
73. Jiang F, Jiang J, He W, et al. Chrysophanol alleviates acute lung injury caused by Klebsiella pneumoniae infection by inhibiting pro-inflammatory cytokine production. Phytother Res 2023;37:2965-78. [Crossref] [PubMed]
74. Hu R, Chen ZF, Yan J, et al. Complement C5a exacerbates acute lung injury induced through autophagy-mediated alveolar macrophage apoptosis. Cell Death Dis 2014;5:e1330. [Crossref] [PubMed]
75. Liu X, Cao H, Li J, et al. Autophagy induced by DAMPs facilitates the inflammation response in lungs undergoing ischemia-reperfusion injury through promoting TRAF6 ubiquitination. Cell Death Differ 2017;24:683-93. [Crossref] [PubMed]
76. Yang L, Zhang Z, Zhuo Y, et al. Resveratrol alleviates sepsis-induced acute lung injury by suppressing inflammation and apoptosis of alveolar macrophage cells. Am J Transl Res 2018;10:1961-75. [PubMed]
77. Qiu P, Liu Y, Chen K, et al. Hydrogen-rich saline regulates the polarization and apoptosis of alveolar macrophages and attenuates lung injury via suppression of autophagy in septic rats. Ann Transl Med 2021;9:974. [Crossref] [PubMed]
78. Qu M, Chen Z, Qiu Z, et al. Neutrophil extracellular traps-triggered impaired autophagic flux via METTL3 underlies sepsis-associated acute lung injury. Cell Death Discov 2022;8:375. [Crossref] [PubMed]
79. Zhao H, Chen H, Xiaoyin M, et al. Autophagy Activation Improves Lung Injury and Inflammation in Sepsis. Inflammation 2019;42:426-39. [Crossref] [PubMed]
80. Zhu CL, Xie J, Zhao ZZ, et al. PD-L1 maintains neutrophil extracellular traps release by inhibiting neutrophil autophagy in endotoxin-induced lung injury. Front Immunol 2022;13:949217. [Crossref] [PubMed]
81. Lorne E, Zhao X, Zmijewski JW, et al. Participation of mammalian target of rapamycin complex 1 in Toll-like receptor 2- and 4-induced neutrophil activation and acute lung injury. Am J Respir Cell Mol Biol 2009;41:237-45. [Crossref] [PubMed]
82. Zhu Q, Wang H, Wang H, et al. Protective effects of ethyl pyruvate on lipopolysaccharide‑induced acute lung injury through inhibition of autophagy in neutrophils. Mol Med Rep 2017;15:1272-8. [Crossref] [PubMed]
83. Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009;137:873-86. [Crossref] [PubMed]