Sepsis is one of the most common pathogenetic causes of acute lung injury (ALI), and at present there is still a lack of effective targeted techniques and methods for its prevention and treatment. Autophagy is a homeostatic mecha- nism common to all eukaryotic cells, including adaption to environment, defense against invasion of pathogens, and maintenance of cellular homeostasis. Autophagy is also involved in a variety of lung-related diseases. In septic lung injury, autophagy not only serves to dissipate dysfunctional organelles, but also inhibits the release of inflammatory cytokines. This review aims at eliciting the role of autophagy in sepsis-induced ALI and further exploring the potential targets of autophagy in inhibiting inflammation, in an effort to provide a new perspective for clinical treatment of sepsis-induced ALI.
Acute Lung Injury ; etiology ; metabolism ; Autophagy ; Cytokines ; metabolism ; Inflammation ; metabolism ; Lung ; metabolism ; Lung Injury ; Sepsis ; complications ; metabolism

Acute Disease ; Cytokines ; metabolism ; Lung Injury ; chemically induced ; Paraquat ; toxicity

Acute pancreatitis (AP) is a common and potentially life-threatening pancreatic inflammatory disease. Although it is usually self-limiting, up to 20% of patients will develop into severe AP. It may lead to systemic inflammatory response syndrome and multiple organ dysfunction, affecting the lungs, kidneys, liver, heart, etc. Surviving patients usually have sequelae of varying degrees, such as chronic hyperglycemia after AP (CHAP), pancreatic exocrine insufficiency, and chronic pancreatitis. Lacking specific target treatments is the main reason for high mortality and morbidity, which means that more research on the pathogenesis of AP is needed. Ferroptosis is a newly discovered regulated cell death (RCD), originally described in cancer cells, involving the accumulation of iron and the depletion of plasma membrane polyunsaturated fatty acids, and a caspase-independent RCD. It is closely related to neurological diseases, myocardial infarction, ischemia/reperfusion injury, cancer, etc. Research in the past years has also found the effects of ferroptosis in AP, pancreatic cancer, and AP complications, such as acute lung injury and acute kidney injury. This article reviews the research progress of ferroptosis and its association with the pathophysiological mechanisms of AP, trying to provide new insight into the pathogenesis and treatment of AP, facilitating the development of better-targeted drugs.
Humans ; Pancreatitis/pathology* ; Acute Disease ; Ferroptosis ; Pancreas/pathology* ; Acute Lung Injury/metabolism*

Sphingosine-1-phosphate (S1P) is the main metabolite produced in the process of phospholipid metabolism, which can promote proliferation, migration, and apoptosis of cells, and maintain the barrier function of vascular endothelium. The latest researches showed that S1P can alleviate acute lung injury (ALI) and the inflammation caused by ALI, while the dosage of S1P is still needed to be considered. Mesenchymal stem cells (MSCs) have been a emerging therapy with potential therapeutic effects on ALI because of their characteristics of self-replication and multi-directional differentiation, and their advantages in hematopoiesis, immune regulation, and tissue repair. S1P can promote differentiation of MSCs and participate in immune regulation, while MSCs can regulate the homeostasis of S1P in the body. The synergistic effect of S1P and MSC provides a new treatment method for ALI. This article reviews the production and biological function of S1P, receptor and signal pathway of S1P, the therapeutic effects of S1P on ALI, and the research advances of S1P combined with MSCs in the treatment of ALI, aiming to provide theoretical references for the development of S1P targeted drugs in the treatment of ALI and the search for new combined treatment schemes for ALI.
Acute Lung Injury ; Animals ; Lung/metabolism* ; Lysophospholipids/pharmacology* ; Mice ; Mice, Inbred C57BL ; Sphingosine/pharmacology*

OBJECTIVE: To investigate protective effect of Cordyceps sinensis (CS) through autophagy-associated adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway in acute kidney injury (AKI)-induced acute lung injury (ALI). METHODS: Forty-eight male Sprague-Dawley rats were divided into 4 groups according to a random number table, including the normal saline (NS)-treated sham group (sham group), NS-treated ischemia reperfusion injury (IRI) group (IRI group), and low- (5 g/kg·d) and high-dose (10 g/kg·d) CS-treated IRI groups (CS1 and CS2 groups), 12 rats in each group. Nephrectomy of the right kidney was performed on the IRI rat model that was subjected to 60 min of left renal pedicle occlusion followed by 12, 24, 48, and 72 h of reperfusion. The wet-to-dry (W/D) ratio of lung, levels of serum creatinine (Scr), blood urea nitrogen (BUN), inflammatory cytokines such as interleukin- β and tumor necrosis factor- α, and biomarkers of oxidative stress such as superoxide dismutase, malonaldehyde (MDA) and myeloperoxidase (MPO), were assayed. Histological examinations were conducted to determine damage of tissues in the kidney and lung. The protein expressions of light chain 3 II/light chain 3 I (LC3-II/LC3-I), uncoordinated-51-like kinase 1 (ULK1), P62, AMPK and mTOR were measured by Western blot and immunohistochemistry, respectively. RESULTS: The renal IRI induced pulmonary injury following AKI, resulting in significant increases in W/D ratio of lung, and the levels of Scr, BUN, inflammatory cytokines, MDA and MPO (P<0.01); all of these were reduced in the CS groups (P<0.05 or P<0.01). Compared with the IRI groups, the expression levels of P62 and mTOR were significantly lower (P<0.05 or P<0.01), while those of LC3-II/LC3-I, ULK1, and AMPK were significantly higher in the CS2 group (P<0.05 or P<0.01). CONCLUSION CS had a potential in treating lung injury following renal IRI through activation of the autophagy-related AMPK/mTOR signaling pathway in AKI-induced ALI.
Rats ; Male ; Animals ; AMP-Activated Protein Kinases/metabolism* ; Cordyceps/metabolism* ; Rats, Sprague-Dawley ; Kidney/pathology* ; Acute Kidney Injury/metabolism* ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism* ; Reperfusion Injury/metabolism* ; Cytokines/metabolism* ; Acute Lung Injury/drug therapy* ; Mammals/metabolism*

The present study explored the mechanism of Fagopyri Dibotryis Rhizoma(FDR) and its main active components in the treatment of acute lung injury(ALI) based on the network pharmacology and the in vitro experiments. The main active components of FDR were obtained from the TCMSP database and screened by oral bioavailability and drug-likeness. The related target proteins of FDR were retrieved from the PubChem database, and the target genes related to ALI were screened out from the GeneCards database. A protein-protein interaction(PPI) network of compound target proteins and ALI target genes was constructed using STRING 11.0. Ingenuity Pathway Analysis(IPA) platform was used to analyze the common pathways of the potential compound target proteins of FDR and ALI target genes, thereby predicting the key targets and potential signaling pathways of FDR for the treatment of ALI. Finally, the potential pathways and key targets were verified by the in vitro experiments of lipopolysaccharide-induced RAW264.7 cells intervened by epicatechin(EC), the active component of FDR. The results of network pharmacology showed that 15 potential active components such as EC, procyanidin B1, and luteolin presumedly functioned in the treatment of ALI through nuclear transcription factor-κB(NF-κB) signaling pathway, transforming growth factor-β(TGF-β) signaling pathway, and adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK) signaling pathway through key targets, such as RELA(P65). The results of in vitro experiments showed that 25 μmol·L~(-1) EC had no toxicity to cells and could inhibit the expression of the p65-phosphorylated protein in the NF-κB signaling pathway to down-regulate the expression of downstream inflammatory cytokines, including tumor necrosis factor-α(TNF-α), IL-1β and nitric oxide(NO), and up-regulate the expression of IL-10. These results suggested that the therapeutic efficacy of FDR on ALI was achieved by inhibiting the phosphorylation of p65 protein in the NF-κB signaling pathway and down-regulating the level of proinflammatory cytokines downstream of the signaling pathways.
Acute Lung Injury/genetics* ; Lipopolysaccharides ; NF-kappa B/metabolism* ; Rhizome ; Signal Transduction

ObjectiveAcute respiratory distress syndrome (ARDS) is an acute and lethal clinical syndrome that is characterized by the injury of alveolar epithelium, which impairs active fluid transport in the lung, and impedes the reabsorption of edema fluid from the alveolar space. This review aimed to discuss the role of pro-resolving mediators on the regulation of alveolar fluid clearance (AFC) in ARDS.

Data SourcesArticles published up to September 2017 were selected from the PubMed, with the keywords of "alveolar fluid clearance" or "lung edema" or "acute lung injury" or "acute respiratory distress syndrome", and "specialized pro-resolving mediators" or "lipoxin" or "resolvin" or "protectin" or "maresin" or "alveolar epithelial cells" or "aspirin-triggered lipid mediators" or "carbon monoxide and heme oxygenase" or "annexin A1".

Study SelectionWe included all relevant articles published up to September 2017, with no limitation of study design.

ResultsSpecialized pro-resolving mediators (SPMs), as the proinflammatory mediators, not only upregulated epithelial sodium channel, Na,K-ATPase, cystic fibrosis transmembrane conductance regulator (CFTR), and aquaporins levels, but also improved Na,K-ATPase activity to promote AFC in ARDS. In addition to the direct effects on ion channels and pumps of the alveolar epithelium, the SPMs also inhibited the inflammatory cytokine expression and improved the alveolar epithelial cell repair to enhance the AFC in ARDS.

ConclusionsThe present review discusses a novel mechanism for pulmonary edema fluid reabsorption. SPMs might provide new opportunities to design "reabsorption-targeted" therapies with high degrees of precision in controlling ALI/ARDS.

Acute Lung Injury ; metabolism ; Animals ; Cystic Fibrosis Transmembrane Conductance Regulator ; metabolism ; Humans ; Respiratory Distress Syndrome, Adult ; metabolism

OBJECTIVETo observe the changes of pulmonary surfactant (PS) in rats with acute lung injury(ALI) induced by lipopolysaccharide (LPS) and to explore the effects of hydrogen sulfide (H2S) on PS.

METHODSFourty- eight male rats were randomly divided into six groups (n = 8). They were control group, LPS group, LPS+ NaHS low, middle, high dose groups and LPS+ PPG group. Saline was administrated in Control group. LPS was administrated in LPS group. In LPS + NaHS low, middle, high dose groups or LPS + PPG group, sodium hydrosulfide (NaHS) of different doses or DL-propargylglycine (PPG) were respectively administrated when the rats were administrated of LPS after 3 hours. All the rats were killed at 6 hours after administration of Saline or LPS. The morphological changes of alveolar epithelial type II cells (AEC-II) were respectively observed by transmission electron microscopes. The content of H2S in plasma and activity of cystathionine-gamma-lyase (CSE) in lung tissues were respectively detected. The contents of total protein (TP) and total phospholipids (TPL) in bronchoalveolar lavage fluid (BLAF) were respectively measured. The pulmonary surfactant protein A (SP-A), surfactant protein B (SP-B) and surfactant protein-C (SP-C) mRNA expressions in lung tissues were analysed.

RESULTS(1) Compared with control group, the content of H2S in plasma, activity of CSE, content of TPL, and SP-A, SP-B and SP-C mRNA expressions were respectively decreased in LPS group (P < 0.05 or P < 0.01). But the content of TP was increased in LPS group (P < 0.01); (2) Compared with LPS group, the content of H2S, activity of CSE and SP-A mRNA expression were significantly increased in LPS + NaHS low, middle and high dose groups (P < 0.05). The SP-B mRNA expression and content of TPL were significantly increased in LPS + NaHS Middle and High dose groups (P < 0.05). The content of TP was decreased in LPS + NaHS High dose group (P < 0.05). The SP-C mRNA expression was not altered in LPS+ NaHS low, middle and high dose groups (P > 0.05); (3) Compared with LPS group, the content of H2S, activity of CSE, content of TPL, and SP-A, SP-B and SP-C mRNA expressions were respectively decreased, but content of TP was increased in LPS + PPG group (P < 0.05).

CONCUSIONThe decrease of PS is the important physiopathologic process of ALI induced by LPS. Exogenously applied H2S could attenuate the process of ALI that possibly because H2S could adjust the compose and secretion of PS.

Acute Lung Injury ; chemically induced ; metabolism ; Animals ; Hydrogen Sulfide ; metabolism ; pharmacology ; Lipopolysaccharides ; Male ; Pulmonary Surfactants ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo confirm the antioxidant protective effect of peroxiredoxin 6 (Prdx6) in acute lung injury in mice.

METHODSLung injury or lung alveolar type II epithelial cell (AEC II) injury models were induced in mice by 100% O2 exposure or H2O2 treatments. Mice and AEC II cell survival rate or BALF analysis were applied for evaluating the degree of acute lung injury. Western Blot assay was used to determine Prdx6 or Gpx1 protein expression in lung. Annexin V staining method was applied to detect cell apoptosis on cultured AEC II cell, and thiobarbituric acid reactive substance (TBARS) measurement and diphenyl-1-pyrenyl phospholine (DPPP) assays were separately used to measure the level of lipid peroxidation in mice lung and AEC II cell membrane.

RESULTSUnder 100% O2 exposure, Prdx6-/- mice presented 24 h shorter survival time compared to wild type (WT) mice, on the contrary, Prdx6 gene over-expressed (Tg Prdx6) mice showed enhanced mice survival; meanwhile, the degree of AEC II cell injury had H2O2-dose dependent pattern with interactive relationship of Prdx6 protection. Under 100% O2 exposure for 72 h, it caused 7-fold decreased Gpx1 expression in Prdx6-/- mouse lung with no remarkable decrease of Prdx6 expression in Gpx1-/- mice. The percentage of apoptotic cells was significantly increased in AEC II cells from Prdx6-/- mice, and the percentage of AEC II apoptotic cells from Tg Prdx6 kept consistently around 10% under H2O treatments; also, the lipid peroxidation level of AEC II cell membrane was the highest in the group of Prdx6-/- mice, which was about 2 or 4-fold increased compared to the groups of WT or Tg Prdx6, separately; meanwhile, the lipid peroxidation level in Prdx6-/- mice, was also the highest compared to the other groups.

CONCLUSIONSPrdx6 plays a critical role in defending acute oxidative lung injury and its function of defending cell apoptosis and cell membrane lipid peroxidation suggests its unique cell-based protective effect.

Acute Lung Injury ; metabolism ; prevention & control ; Animals ; Antioxidants ; metabolism ; Apoptosis ; Hydrogen Peroxide ; metabolism ; Lipid Peroxidation ; Lung ; drug effects ; metabolism ; Male ; Mice ; Mice, Knockout ; Peroxiredoxin VI ; metabolism

Objective To explore the effect and mechanism of penehyclidine hydrochloride (PHCD) on vascular endothelial injury in septic rats. Methods Fifty male SD rats were randomly divided into control group, lipopolysaccharide (LPS) induced sepsis group (model group), low dose PHCD (0.3 mg/kg) group, medium dose PHCD (1.0 mg/kg) group and high dose PHCD (3.0 mg/kg) groups, ten mice for each group. Normal saline was injected into the tail vein of the control group, and 10 mg/kg lipopolysaccharide (LPS) was injected into the tail vein of the rats in other groups to prepare the sepsis rat models. After the models were successfully established, low, medium and high doses (0.3, 1.0, 3.0 mg/kg) of PHCD solution were injected into the tail vein of the rats of corresponding groups. Wet/dry mass ratio (W/D) of lung tissue of rats in each group was measured, and ELISA was used to assay interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 content and rat plasma angiopoietin 2 (Ang2) content in bronchoalveolar lavage fluid (BALF). HE staining was used to observe the pathological changes of lung tissues. Immunohistochemical staining was used to observe the expression of Ang2 in the right lung tissues. Western blot analysis was performed to detect Ang2 and vascular endothelial cadherin (VE-cadherin) protein in lung tissues. Results Compared with the control group, the W/D ratio of the lung tissues of rats in the model group and the contents of IL-1β, IL-6 and TNF-α in BALF were significantly increased; the lung tissues showed obvious pathological damage, with up-regulation of Ang2 expression and down-regulation of VE-Cadherin expression. Compared with the model group, the W/D ratio of the lung tissues of rats in three PHCD treatment groups and the contents of IL-1β, IL-6 and TNF-α in BALF were significantly reduced; the pathological damage of lung tissue was significantly reduced, with down-regulation of Ang2 expression and up-regulation of VE-cadherin expression. Conclusion PHCD can reduce LPS-induced lung inflammation in rats with sepsis by regulating the Ang2/VE-Cadherin pathway, thereby improving vascular endothelial injury.
Rats ; Mice ; Animals ; Male ; Lipopolysaccharides/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Angiopoietin-2/pharmacology* ; Interleukin-6/metabolism* ; Rats, Sprague-Dawley ; Lung ; Acute Lung Injury/metabolism* ; Sepsis/metabolism*