Microbes and Infection 16 (2014) 727e734 www.elsevier.com/locate/micinf

Review

mTOR and autophagy in regulation of acute lung injury: a review and perspective Yue Hu a, Juan Liu a, Yin-Fang Wu a, Jian Lou a, Yuan-Yuan Mao a, Hua-Hao Shen a,b,*, Zhi-Hua Chen a,* a

Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China b State Key Lab of Respiratory Diseases, Guangzhou, China Received 30 April 2014; accepted 18 July 2014 Available online 30 July 2014

Abstract The mammalian target of rapamycin (mTOR) is a central regulator of many major cellular processes including protein and lipid synthesis and autophagy, and is also implicated in an increasing number of pathological conditions. Emerging evidence suggests that both mTOR and autophagy are critically involved in the pathogenesis of pulmonary diseases including acute lung injury (ALI). However, the detailed mechanisms of these pathways in disease pathogenesis require further investigations. In certain cases within the same disease, the functions of mTOR and autophagy may vary from different cell types and pathogens. Here we review recent advances about the basic machinery of mTOR and autophagy, and their roles in ALI. We further discuss and propose the likelihood of cell type- and pathogen-dependent functions of these pathways in ALI pathogenesis. © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Keywords: mTOR; Autophagy; Acute lung injury

1. Introduction The mammalian target of rapamycin (mTOR) and one of its major downstream processes autophagy are central regulators of cellular metabolism, proliferation, and survival, which are implicated in various proliferative and metabolic diseases, including obesity, type 2 diabetes, hamartoma syndromes, neurodegenerative diseases, and cancer [1,2]. To date, the functions of mTOR and autopahgy have been studied in pulmonary diseases, including acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary arterial hypertension (PAH), tuberculosis, * Corresponding authors. Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Rd, Hangzhou 310009, China. Tel.: þ86 571 8898 1913; fax: þ 86 571 8778 3729. E-mail addresses: [email protected] (H.-H. Shen), zhihuachen2010@ 163.com (Z.-H. Chen).

lymphangioleiomyomatosis, and lung cancer [3e5]. ALI is a spectrum of lung diseases associated with an acute inflammatory process and characterized by a disruption of the pulmonary microvascular barrier [6]. Although there are many studies about ALI, the current therapeutic strategies for ALI are still very sparse and mortality remains high. This review first gives an introduction to the basic regulatory machinery of the mTOR and autophagy pathways, and then describes the potential association of these signaling pathways with ALI development. Given the cell- and stimulusdependent nature of mTOR and autophagy, we discuss and propose the likelihood of cell type- and pathogen-dependent functions of these pathways in ALI pathogenesis. 2. Signaling pathways in regulation of the mTORautophagy cascade mTOR, as its name suggests, is the target of a molecule named rapamycin or sirolimus. It is an atypical serine/

http://dx.doi.org/10.1016/j.micinf.2014.07.005 1286-4579/© 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

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threonine protein kinase belonging to the phosphoinositide 3kinase (PI3K)-related kinase family. This molecule interacts with several proteins to form two distinct complexes referred to as mTOR complex1 (mTORC1) and 2 (mTORC2). These complexes both contain the catalytic mTOR subunit, the mammalian lethal with sec-13 protein 8 (mLST8) [7], the DEP domain containing mTOR-interacting protein (DEPTOR) [8], and the Tti1/Tel2 complex [9]. Specifically, mTORC1 contains the regulatory-associated protein of the mammalian target of rapamycin (raptor) [10] and the proline-rich Akt substrate 40 kDa (PRAS40) [11], whereas mTORC2 comprises the rapamycin-insensitive companion of mTOR (rictor) [12], the mammalian stress-activated map kinase-interacting protein 1 (mSin1) [13], and the protein observed with rictor 1 and 2 (protor1/2) [14]. The complexes have different sensitivities to rapamycin as well as upstream inputs and downstream outputs. In general, mTORC1 activates p70S6 kinase (p70S6K) and inhibits the eukaryotic transcriptional initiation factor 4Ebinding protein 1(4E-BP1) in a rapamycin sensitive fashion. On the contrary, mTORC2 controls the organization of the actin cytoskeleton and is rapamycin insensitive [1,15e17]. Moreover, rapamycin has been reported to disrupt mTORC2 in vivo, and this process appears to mediate rapamycininduced insulin resistance [18]. The heterodimer tuberous sclerosis complex 1/2 (TSC1/2) appears to be the central upstream regulator of mTORC1, which functions as a GTPase-activating protein for the Ras homolog enriched in the brain (Rheb) GTPase (Fig. 1) [1,16]. The GTPbound form of Rheb directly interacts with mTORC1 and strongly stimulates its kinase activity. The most studied upstream regulatory pathways of TSC1/2 include PI3K/Akt, Ras, and the adenosine 5’-monophosphate-activated protein kinase (AMPK) [1,15e17]. PI3K/Akt and Ras/ERK directly phosphorylate TSC1/2 complex to inactivate it and then activate mTORC1. Glucose starvation activates LKB1, which then phosphorylates AMPK. Subsequently, the activated AMPK inhibits mTORC1 through phosphorylation. Consistent with the negative function of AMPK in mTORC1 signaling, AMPK positively regulates autophagy in mammalian cells. Akt and AMPK can also regulate mTORC1 independent of TSC1/2 (Fig. 1). Akt phosphorylates PRAS40 and causes its dissociation from raptor [11,19], while AMPK directly phosphorylates raptor, leading to the allosteric inhibition of mTORC1 [20]. mTORC1 is considered as the major negative regulator of autophagy (Fig. 1), which interacts with and phosphorylates ULK1 [1,21e23], the mammalian uncoordinated-51-like protein kinase. ULK1 forms the mTOR substrate complex to negatively regulate autophagy through interaction with mTORC1, Atg13, Atg101, and focal adhesion kinase familyeinteracting protein (FIP200) [24e26]. The activation of ULK1 also recruits the class III PI3K complex to form autophagosomes. mTORC1 and class III PI3K complexes, which then join the elongation phase of autophagosome formation. However, prolonged starvation has been known to reactivate mTOR, which in turn attenuates autophagy and regenerates functional lysosomes [27].

Fig. 1. Major upstream signalings in regulation of autophagy through mTOR. Extracellular inputs, such as growth factors and nutrients, stimulate the PI3K and Ras pathways, and their downstream effectors Akt and Erk directly phopshorylate TSC1/2 and inactivate this complex. On the other side, intracellular stresses, such as low energy and oxygen, activate TSC1/2 through AMPK. TSC1/2 inactivates Rheb and mTOR, and subsequently activates autophagy.

The autophagic pathway proceeds through several phases, including initiation (formation of an isolation membrane), elongation, autophagosome formation and completion, and autophagosome-lysosome fusion. More than 30 autophagy related genes (ATGs) are identified to play pivotal roles in diverse stages of autophagy (Ref. [3], and related references therein). Current available animal tools for autophagy deficiency include knockout or heterozygous impairment of Beclin-1 (ATG6), ATG3, ATG4, ATG5, ATG7, LC3B (ATG8), and ATG16L. 3. The pathogenesis of acute lung injury Acute lung injury is characterized by an uncontrolled acute inflammation and dysfunctions of endothelial and epithelial barriers of the lung, and an excessive transepithelial leukocyte migration, leading to the loss of alveolar-capillary membrane integrity and overproduction of pro-inflammatory cytokines

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[28e30]. ALI is associated with sepsis, hyperoxia, trauma, pharmaceutical or xenobiotic exposure, and mechanical ventilation. According to the American-Europe Consensus Criteria Joint Meeting of ALI diagnostic criteria, the annual incidence of ALI was about 78.9/100,000 in the United States in 2005 [6]. More importantly, current treatments for ALI are still limited to basic medical or surgical therapies to improve ventilation management, yet curative therapy for ALI exists [29,31,32]. The pathogenesis of ALI is explained by injury to both the vascular endothelium and alveolar epithelium. The cells of the innate immune system are both targets of damage and effectors of injury in ALI/Acute Respiratory Distress Syndrome (ARDS). Alveolar epithelial injury of type I cells contributes to pulmonary edema, and the breakdown of this epithelial barrier exposes the underlying basement membrane, predisposing to bacteremia and sepsis. Injury to type II alveolar cells leads to impaired surfactant synthesis and metabolism resulting in increased alveolar surface tension and alveolar collapse [28]. A variety of biomarkers, for example, von Willebrand factor (vWf), intracellular adhesionmolecule-1 (ICAM-1), surfactant D (SP-D), and the receptor for advanced glycation end-products (RAGE), found on the epithelium and endothelium are involved in the inflammatory and coagulation cascades, so predict morbidity and mortality in ALI [33e39]. Protein C and plasminogen activator inhibitor-1 with abnormalities in the coagulation cascade are also characteristics in ALI/ARDS [40]. Following these factors, high expression of pro-inflammatory mediators, such as interleukin-1 (IL-1), IL6, IL-8, and tumor necrosis factor (TNF), have been considered a direct response of cellular injury [41,42]. Of the leukocytes, neutrophils play an important role in the pathogenesis of ALI/ARDS. Neutrophils stimulated with lipopolysaccharide (LPS) or TNF-a showed an activation of nuclear factor kappa B (NF-kB), p38, and AKT, and early alterations in neutrophil activation are associated with ventilator time and survival in ALI patients [43,44]. When activated, neutrophils release harmful mediators including cytokines, chemokines, proteases, reactive oxygen species, and matrix metalloproteinases, which are able to induce the expression of surface molecules on the endothelium and further promote polymorphonuclea (PMN) recruitment [45]. TNF-a, IL-1b, MIP-2, and IL-8 are important neutrophilrelated cytokines found regularly in the BALF of ALI patients at higher concentrations than in their plasma [45]. Excessive activation of neutrophils also contributes to membrane damage and increased permeability of the epithelial barrier. Neutrophils release damaging pro-inflammatory and pro-apoptotic mediators that act on adjacent cells to create ulcerating lesions [46,47]. Alveolar macrophages are also thought to be important in the inflammatory pathways that lead to cell damage in ALI. Large amounts of cytokines including TNF-a, IL-1b, IL-6, IL8 and interferon g, are produced in macrophages which contribute to the initiation of ALI. However, alveolar macrophages can also exert an effect on- the resolution of lung

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injury. Resident and recruited macrophages play an important role in clearance of both injured tissue and PMNs via phagocytosis [48]. More recent reports suggest that lung macrophages are the main orchestrators of termination and resolution of inflammation. They are also initiators of the parenchymal repair process that is essential for returning to homeostasis with normal gas exchange [49]. 4. Roles and mechanisms of mTOR and autophagy in ALI Accumulating evidence has suggested that mTOR and autophagy play important roles in ALI pathogenesis, but their eventual functions in regulation of ALI remain controversial (Table 1). Most of the mechanistic studies focus on epithelial cells or macrophages exploring the functions of mTOR and/or autophagy in regulation of cell death and/or inflammation (Table 1). Given the facts that activation/inactivation of mTOR and autophagy depends on various stimuli and varies in different cell types, and that these pathways differentially orchestrate outcomes (e.g. inflammation or cell death), it is not surprising that the eventual roles of mTOR and autophagy are highly inconsistent in different models of ALI. We discuss the distinct roles and possible mechanisms of mTOR and autophagy in diverse cell types (epithelial cells, endothelial cells, alveolar macrophages, and neutrophils) participating in ALI, as well as in the systemic injury models. 4.1. Epithelial cells Normally, alveolar epithelial cells regulate the epithelial barrier and form cell junctions. The disruption of Type I and II epithelial cells leads to fluid transport and permeability of the epithelial barrier [28e30]. Since excessive autophagy contributes to programmed cell death [50], current mTOR and autophagy related studies in epithelial cells mostly focused on this process. Li et al. [51] observed that nanoparticles triggered autophagic cell death by deregulating the Akt-TSC2mTOR signaling pathway, and the autophagy inhibitor 3methyladenine (3-MA) rescued the nanoparticle-induced epithelial cell death and ameliorated the acute lung injury in mice. Two groups [52,53] reported that H5N1 infection also induced autophagic cell death in lung epithelial cells, together with the suppression of mTOR [52] or activation of the AktTSC [53] pathways. Blocking autophagy not only reduced the epithelial cell death, but also meliorated H5N1-induced acute lung injury and mortality [53]. A more recent study [54] also found that autophagy mediated H5N1-induced production of pro-inflammatory cytokines and chemokines in epithelial cells, and inhibition of autophagy attenuated H5N1induced inflammation in vitro and in vivo. Two studies have investigated the role of autophagy in hyperoxia-induced epithelial cell death [55,56]. Hyperoxia markedly induced autophagosome formation in Beas-2B cells, and LC3B siRNA promoted hyperoxia-induced cell death, whereas overexpression of LC3B conferred cytoprotection [55]. In the context of the carbon monoxide (CO)-induced protection of hyperoxic stress, LC3B-siRNA also attenuated

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Table 1 Major studies of mTOR and autophagy in ALI or ALI-related processes. Reference

ALI model(s) or related processes

Targeted cell type(s) or tissue

Major outcome(s) related to mTOR and autophagy

Li C et al., 2009 [51]

Nanoparticle

Epithelial cell

Ma et al., 2011 [52]

H5N1 infection

Epithelial cell

Lee et al., 2011 [56]

Hyperoxic stress

Epithelial cell

Sun Y et al., 2012 [53]

H5N1 infection

Epithelial cell

Tanaka et al., 2012 [55]

Hyperoxic stress

Epithelial cell

Pan et al., 2014 [54]

Epithelial cell

Nakahira et al., 2011 [65]

H5N1 pseudo typed viral particles LPS

Harris et al., 2011 [66]

LPS

Macrophage

Peral de Castro et al., 2012 [67] Chuang et al., 2013 [68]

TLR mediated injury TLR mediated injury

Macrophage and dendritic cell Macrophage

Lee et al., 2014 [69]

CO in protection of CLP sepsis

Macrophage and Lung

Lorne et al., 2009 [70]

LPS, PAM

Neutrophil

Gomez-Cambronero et al., 2003 [71] Wang et al., 2011 [72]

GM-SCF induced chemotaxis LPS

Neutrophil

Fielhaber et al., 2012 [73]

LPS

Lung

Yen et al., 2013 [74]

CLP

Lung

Lo et al., 2013 [75]

CLP

Lung

Liu et al., 2013 [76] Hussain et al., 2010 [77]

Seawater VILI

Lung Lung

L opez-Alonso et al., 2013 [78] Moy et al., 2014 [79]

VILI

Lung

RVFV

Drosophila and mammalian cells

Nanoparticle triggered autophagic cell death through Akt-TSC2-mTOR pathway, and 3-MA ameliorated nanoparticle-induced cell death and acute lung injury H5N1 caused autophagic cell death through suppression of mTOR, and inhibition of autophagy significantly reduced H5N1 mediated cell death. LC3B-siRNA attenuated the protective effect of CO against hyperoxia-induced cell death H5N1 infection induced autophagy through Akt-TSC pathway, and blocking autophagy ameliorated H5N1 induced cell death, acute lung injury, and mortality LC3B siRNA promoted hyperoxia-induced cell death, whereas overexpression of LC3B conferred cytoprotection Blocking autophagy attenuated H5N1pp-induced pro-inflammatory mediators in vitro and in vivo. Inhibition of autophagy promoted LPS induced inflammasome, and LC3Bdeficient mice produced more cytokines and were susceptible to LPS-induced mortality. Pro-IL-1b was specifically sequestered into autophagosomes, and rapamycin induced the degradation of pro-IL-1b and blocked secretion of the mature cytokine Inhibition of autophagy augmented the secretion of IL-23 in macrophages and dendritic cells in response to specific TLR agonists Overexpressing Beclin 1 in PAI-2-deficient cells rescued the suppression of NLRP3 activation in response to LPS. Beclin1±mice were more susceptible to CLP-induced sepsis, and CO-enhanced bacterial phagocytosis in vivo and in cultured macrophages was dependent on autophagy mTORC1 was activated in bone marrow neutrophils cultured with the LPS and PAM, and rapamycin inhibited PAM- and LPS-induced cytokines and lung injury GM-SCF increased phosphorylation of the p70S6K, and its inhibitor decreased GMeCSFeinduced neutrophil migration Rapamycin reduced TNF-a and IL-6 in the BALF, while it had limited effects on the overall severity of ALI and mortality. Rapamycin increased lung injury and cellular apoptosis, while inhibited NF-kB and neutrophilic inflammation Autophagy was suppressed after CLP, and rapamycin limited the CLP-induced pro-inflammatory response and apoptotic activity Transgenic mice overexpressing LC3 increased clearance of autophagosomes and improved survival after CLP Inhibition of autophagy by 3-MA partly ameliorated seawater-induced ALI Ventilation induced autophagy, which was associated with increased protein oxidation and enhanced expression of the FOXO1 gene Mechanical ventilation increased autophagy and Atg4b/- animals showed a decreased lung injury after ventilation. Viral replication was increased in the absence of autophagy genes in Drosophila, and Pharmacologic activation of autophagy inhibited RVFV infection in mammalian cells.

Macrophage and Lung

Lung

the protective effect of CO against hyperoxia-induced cell death [56]. Interestingly, an early study from the same group reported that in Beas-2B cells, blocking autophagy, including using LC3B-siRNA, attenuated cigarette smoke extractinduced cell death and apoptosis [57]. All above studies suggest that in epithelial cells the functions of autophagy are pathogen-dependent, being either deleterious [51e54,57] or cytoprotective [55,56]. The reasons for such an inconsistence remain unknown. Given the fact that nanomaterials and virus, and maybe cigarette smoke extract, are endocytosed into epithelial cells while hyperoxia induced cell damage may not require endocytosis, there might be some clues based on the link between autophagy and endocytosis in

epithelial cells [58,59]. It might be noteworthy that in certain cases LC3 is required for phagocytosis [60]. Thus, it is plausible that the knockdown of LC3 or inhibition of autophagy may attenuate the internalization of nanomaterials and virus in epithelial cells. 4.2. Endothelial cells The vascular endothelial cells of the lung play a critical role in the semi-permeable barrier between the vascular, interstitial, and alveolar spaces, and injury of vascular endothelial cells lead to increased capillary permeability [61]. Surprisingly, there are very limited studies focusing on the

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role of mTOR and autophagy in lung microvascular endothelial cells in the context of ALI. Only one related study has reported that mice with knockdown of autophagic protein LC3B display an exaggerated pulmonary hypertension during hypoxia [62]. Since mTOR and autophagy have been known to play important roles in vascular endothelial cells [63,64], it is anticipated that these pathways should also function critically in lung microvascular endothelial cells, and should exert effects on ALI pathogenesis. However, for such investigations, endothelial cell specific gene alternation might be necessary to clearly clarify their roles in endothelium during ALI.

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Recently, Lorne et al. [70] found that mTORC1 was dose- and time-dependently activated in bone marrow neutrophils cultured with the TLR4 ligand, LPS, or the TLR2 ligand, Pam3 Cys-Ser-(Lys)4 (PAM).Furthermore, rapamycin inhibited PAM- or LPS-induced cytokine production in cultured neutrophils in vitro and lung injury in vivo [70]. Another related work [71] demonstrated that GMeCSF can act as a neutrophil chemotactic agent and induce neutrophil migration, and the mTOR/S6K pathway appeared to pivotally regulate the GMeCSFeinduced neutrophil migration. These findings altogether indicate that mTOR is required for the recruitment and activation of neutrophils, and may serve as an effective therapeutic target for ALI.

4.3. Macrophages 4.5. Systemic injury models Macrophages usually reside in the lung interstitium and alveoli, and can be recruited into the lung upon inflammatory stimuli. The role of alveolar macrophages in initiating and maintaining pulmonary inflammation during infection or injury has been convincingly demonstrated. Recently, the roles of autophagy in macrophagy during ALI have been studied. Nakahira and colleagues [65] found that autophagy played a key role in limiting the LPS-induced inflammasome response in macrophages. They demonstrated that autophagy deficiency led to an accumulation of dysfunctional mitochondria in macrophages, which subsequently activated the NALP3 inflammasome and induced the production of IL-1b and IL-18. LC3B-deficient mice had higher expression of these cytokines and increased mortality in response to LPS [65]. Intriguingly, Harris et al. [66] found that pro-IL-1b was specifically sequestered into autophagosomes, and rapamycin induced the degradation of pro-IL-1b and blocked secretion of the mature cytokine, suggesting that in addition to regulation of the activation of the NLRP3 inflammasome, autophagy also controls the lysosomal degradation of pro-IL-1b. Similarly, Peral de Castro and colleagues [67] observed that inhibition of autophagy augmented the secretion of IL-23 in macrophages and dendritic cells in response to specific TLR agonists. Furthermore, Chuang et al. [68] demonstrated that TLR2 or TLR4 agonists induced PAI-2 expression, which subsequently stabilized the autophagic protein Beclin 1 to promote autophagy, and overexpressing Beclin 1 in PAI-2deficient cells rescued the suppression of NLRP3 activation in response to LPS. In a model of cecal ligation and puncture (CLP)-induced sepsis, Lee et al. [69] found that Beclin1þ/ mice were more susceptible, and CO-enhanced bacterial phagocytosis in vivo and in cultured macrophages was dependent on autophagy. All the above findings suggest that in macrophages, induction of autophagy plays a protective role against various pathogens, although the detailed molecular mechanisms require further investigations. 4.4. Neutrophils One of the cardinal features of ALI is excessive transepithelial leukocyte migration, most of which are neutrophils.

A number of studies explored the role of mTOR and autophagy in diverse animal models of ALI, without detailed cell specific mechanistic investigation. Most of these studies used pharmacological compounds such as rapamycin and the autophagy inhibitor 3-methyladenine (3-MA), and the eventual roles of these compounds vary from different studies. In LPS-induced ALI, Wang et al. [72] found that rapamycin reduced the levels of TNF-a and IL-6 in the BALF, while it had limited effects on the overall severity of ALI and mortality. Another study [73] reported that rapamycin increased lung injury and cellular apoptosis, while inhibited NF-kB and neutrophilic inflammation. Apparently, rapamycin, likely through mTOR, plays different roles in different cells during ALI. In a CLP-induced injury model, Yen and colleagues [74] observed that autophagy was suppressed after CLP, and rapamycin limited the CLP-induced pro-inflammatory response and apoptotic activity. Consistent with this, transgenic mice overexpressing LC3 exhibited an increased clearance of autophagosomes and displayed an improved survival after CLP [75]. These data suggest that inhibition of mTOR and induction of autophagy concordantly protect CLP-induced injury in vivo. A more recent study explored the role of autophagy in seawater-induced ALI [76]. They found that autophagy was significantly induced by seawater in the airway epithelial cells, and inhibition of autophagy by 3-MA partly ameliorated seawater-induced injury. These results indicate a deleterious effect of autophagy in epithelial injury in seawater-induced ALI, which is consistent with the cases of nanomaterials, virus, and cigarette smoking [51e54,57]. A couple of studies also investigated the role of autophagy in ventilation-induced lung injury (VILI). Hussain and colleagues [77] observed that prolonged ventilation triggered autophagy activation, and the induction of autophagy was associated with increased protein oxidation and enhanced expression of the FOXO1 gene, but not the FOXO3A gene. A later study [78] also confirmed such an autophagy induction by VILI, and further demonstrated that ATG4/ animals were protected after ventilation, which was likely through downregulation of the NF-kB signaling.

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Fig. 2. Schemata about the roles of mTOR and autophagy in ALI. Black arrows and words indicate established relationships, whereas red ones indicate proposed regulation. Various stimuli orchestrate the mTOR and autophagy in a cell dependent manner, and in each cell type, the eventual roles of these molecules may also vary upon the outcomes.

Most recently, Moy et al. [79] demonstrated that autophagy exerted an antiviral capacity from flies to mammals. Infection with Rift Valley fever virus (RVFV) elicited autophagy in Drosophila, and viral replication was increased in the absence of autophagy genes. Pharmacologic activation of autophagy also inhibited RVFV infection in mammalian cells.

5. Conclusion remarks Although our knowledge of the science of mTOR and autophagy in human diseases including ALI is rapidly progressing, future studies are encouraged to address the following issues. 1) Current available evidence strongly indicates that the role of mTOR and autophagy in disease pathogenesis including ALI are extremely cell- and pathogendependent (Fig. 2), and thus cell specific alteration of related genes is crucial for clarifying their eventual function in ALI induced by different pathogens. 2) Ideally, exogenous modulation of mTOR and autophagy in mechanistic study or treatment of diseases needs to be similarly selective, as current approaches using rapamycin or 3-MA in vivo are never cell-specific. 3) Little is known about the roles of these pathways in other cells such as endothelial cells, fibroblasts, and other immune cells which are also very important in ALI

pathogenesis (Fig. 2). 4) Challenges remain to understand the basic mechanisms behind mTOR and autophagy which play different roles within the same cells upon different stimuli. 5) Given the way that mTOR orchestrates downstream signals, whether the effect of mTOR (e.g. rapamycin treatment) in ALI is solely through regulation of autophagy needs to be clarified. In other words, is mTOR activity responsible for autophagy expression in each existing current autophagyrelated ALI model? Nevertheless, although no ideal mTORand autophagy-related tools are currently available for clinical use for ALI or other diseases, these pathways are inevitably the foundation of new diagnostic targets and treatment strategies. Competing interests The authors declare that they have no competing interests. Acknowledgments This work was supported in part by the General Project 81370142 (to Z. H. C.) and the Key Project 81130001 (to H. H. S.) from the National Natural Science Foundation of China, and project from the National Clinical Research Center of China for Respiratory Disease.

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mTOR and autophagy in regulation of acute lung injury: a review and perspective.

The mammalian target of rapamycin (mTOR) is a central regulator of many major cellular processes including protein and lipid synthesis and autophagy, ...
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