Pathophysiology Of Acute Lung Injury Research Articles

PTPRO inhibits LPS-induced apoptosis in alveolar epithelial cells

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), represent critical clinical syndromes with multifactorial origins, notably stemming from sepsis within intensive care units (ICUs). Despite their high mortality rates, no selective cure is available beside ventilation support. Apoptosis plays a complex and pivotal role in the pathophysiology of acute lung injury. Excessive apoptosis of alveolar epithelial and microvascular endothelial cells can lead to disruption of lung epithelial barrier integrity, impairing the body's ability to exchange blood and gas. At the same time, apoptosis of damaged or dysfunctional cells, including endothelial and epithelial cells, can help maintain tissue integrity and accelerate recovery from organ pro-inflammatory stress. The balance between pro-survival and pro-apoptotic signals in lung injury determines patient outcomes, making the modulation of apoptosis an area of intense research in the quest for more effective therapies. Here we found that protein tyrosine phosphatase receptor type O (PTPRO), a poorly understood receptor-like protein tyrosine phosphatase, is consistently upregulated in multiple tissue types of mice under septic conditions and in the lung alveolar epithelial cells. PTPRO reduction by its selective short-interfering RNA (siRNA) leads to excessive apoptosis in lung alveolar epithelial cells without affecting cell proliferation. Consistently PTPRO overexpression by a DNA construct attenuates apoptotic signaling induced by LPS. These effects of PTPTO on cellular apoptosis are dependent on an ErbB2/PI3K/Akt/NFκB signaling pathway. Here we revealed a novel regulatory pathway of cellular apoptosis by PTPRO in lung alveolar epithelial cells during sepsis.

Sex differences in Acute Lung Injury (ALI)-Induced Respiratory Functional Changes in a Bleomycin Rat Model

Introduction: Acute lung injury (ALI) is a pathology characterized primarily by profound disruption of the epithelial-endothelial interface, leukocyte migration into the alveolar space, leading to disordered gas exchange and consequential respiratory failure. There exist several animal models to study the pathophysiology of ALI. Bleomycin, a cancer therapeutic, has been shown to consistently induce the ALI phenotype in rodent models. We have previously shown that intra-tracheal bleomycin instillation in rats produces deleterious changes in respiratory function in both acute and recovery phases of ALI. In this study, we sought to elucidate the effect of sex bleomycin-induced ALI. Methods: To do this, cohorts of male and female Sprague-Dawley rats were measured using whole-body plethysmography (WBP) where the following respiratory parameters were recorded prior to bleomycin exposure (Week 0): Volume of Oxygen consumed normalized to body weight (VO2/kg), Respiratory rate (RR), Tidal Volume normalized to body weight (TV/kg), Minute Ventilation normalized to body weight (MV/kg), enhanced pause (Penh), pause (PAU), ratio rate of achieving peak expiatory flow (Rpef), peak inspiratory flow (box) (PIFb), peak expiratory flow box (PEFb), inspiratory time (Ti), expiratory time (Te), expiratory flow at the point of 50%TV (EF50), end-inspiratory pause (EIP), end-expiratory pause (EEP), relaxation time (Tr) and time of brake (TB). A single dose of intra-tracheal bleomycin (2.5mg/kg) was instilled and subsequent WBP recordings were performed weekly during the acute phase of ALI (Week 1), and the recovery phase of ALI (Week 4). Results: Our results show that bleomycin-induced ALI resulted in greater DTE (Weeks 1-3) and DTR (Weeks 1-2) in females compared to males. Measures of airway obstruction were also shown to be sex-dependent, as DRpef (Week 1), DPAU (Weeks 2-4), and DPenh (Weeks 2-4) were significantly different between males and females. EF50, a metric highly correlated with lung pathologies, remained unchanged between sexes post-ALI. While inducing ALI did not alter DPIFb between the sexes, DPEFb was elevated among males compared to females (Weeks 2,4). DEIP and DEEP both showed sex-dependent changes post-ALI, with females displaying a greater decrease compared to males. Additionally, there was a greater decrease in DTV/kg among females compared to males post-ALI (Weeks 1-3). DRR, DMV/kg, and DVO2/kg were unchanged across the 4 weeks post-ALI between sexes. Conclusion: Our study reveals sex-specific nuances in bleomycin-induced acute lung injury (ALI) in Sprague-Dawley rats. Differential responses in airway obstruction measures and distinct impacts on respiratory dynamics underscore the importance of considering sex in researching ALI. This work is supported by NIH R01HL152160-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

RIPK1 inhibitor ameliorates pulmonary injury by modulating the function of neutrophils and vascular endothelial cells

Acute lung injury (ALI) is an acute and progressive hypoxic respiratory failure that could progress to acute respiratory distress syndrome (ARDS) with a high mortality rate, thus immediate medical attention and supportive care are necessary. The pathophysiology of ALI is characterized by the disruption of the alveolar-capillary barrier and activation of neutrophils, leading to lung tissue damage. The receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising target for the treatment of multiple inflammatory diseases, but the role of RIPK1 in the ALI remains poorly understood. In this study, we aimed to figure out the pathological role of RIPK1 in ALI, especially in the pulmonary immune microenvironment involving neutrophils and endothelial cells. In vivo experiments showed that RIPK1 inhibitor protected against lipopolysaccharide (LPS)-induced lung injury in mouse models, with reduced neutrophils and monocytes infiltration in the lungs. Further studies demonstrated that, besides the inhibitory action on necroptosis, RIPK1 inhibitor directly suppressed reactive oxygen species (ROS) generation and inflammatory cytokines secretion from neutrophils. Furthermore, RIPK1 inhibition maintains the barrier function in TNF-α-primed vascular endothelial cells and prevents their activation induced by the supernatant from LPS-stimulated neutrophils. Mechanistically, the aforementioned effects of RIPK1 inhibitor are associated with the NF-κB signaling pathway, which is partially independent of necroptosis inhibition. These results provide new evidence that RIPK1 inhibitor directly regulates the function of neutrophils and endothelial cells, as well as interferes with the interactions between these two cell types, therefore contributing to a better understanding of RIPK1 in ALI and providing a potential avenue for future therapeutic interventions.

Screening Therapeutic Effects of MSC-EVs to Acute Lung Injury Model on A Chip.

Acute lung injury (ALI) is a lethal disease with high mortality rate, and its physiologically relevant models that could mimic human disease processes are urgently needed to study pathophysiology and predict drug efficacy. Here, this work presents a novel lipopolysaccharide(LPS) based ALI model on a microfluidic chip that reconstitutes an air-liquid interface lined by human alveolar epithelium and microvascular endothelium for screening the therapeutic effects of mesenchymal stem cells (MSC) derived extracellular vesicles (MSC-EVs) to the biomimetic ALI. The air-liquid interface is established by coculture of alveolar epithelium and microvascular endothelium on the opposite sides of the porous membrane. The functionalized architecture is characterized by integrate cell layers and suitable permeability. Using this biomimetic microsystem, LPS based ALI model is established, which exhibits the disrupted alveolar-capillary barrier, reduced transepithelial/transendothelial electrical resistance (TEER), and impaired expression of junction proteins. As a reliable disease model, this work examines the effects of MSC-EVs, and the data indicate the therapeutic potential of EVs for severe ALI. MSC-EVs can alleviate barrier disruption by restoring both the epithelial and endothelial barrier integrity. They hope this study can become a unique approach to study human pathophysiology of ALI and advance drug development.

Gossypin mitigates oxidative damage by downregulating the molecular signaling pathway in oleic acid-induced acute lung injury.

One of the leading causes of acute lung injury, which is linked to a high death rate, is pulmonary fat embolism. Increases in proinflammatory cytokines and the production of free radicals are related to the pathophysiology of acute lung injury. Antioxidants that scavenge free radicals play a protective role against acute lung injury. Gossypin has been proven to have antioxidant, antimicrobial, and anti-inflammatory properties. In this study, we compared the role of Gossypin with the therapeutically used drug Dexamethasone in the acute lung injury model caused by oleic acid in rats. Thirty rats were divided into five groups; Sham, Oleic acid model, Oleic acid+Dexamethasone (0.1 mg/kg), Oleic acid+Gossypin (10 and 20 mg/kg). Two hours after pretreatment with Dexamethasone or Gossypin, the acute lung injury model was created by injecting 1 g/kg oleic acid into the femoral vein. Three hours following the oleic acid injection, rats were decapitated. Lung tissues were extracted for histological, immunohistochemical, biochemical, PCR, and SEM imaging assessment. The oleic acid injection caused an increase in lipid peroxidation and catalase activity, pathological changes in lung tissue, decreased superoxide dismutase activity, and glutathione level, and increased TNF-α, IL-1β, IL-6, and IL-8 expression. However, these changes were attenuated after treatment with Gossypin and Dexamethasone. By reducing the expression of proinflammatory cytokines and attenuating oxidative stress, Gossypin pretreatment provides a new target that is equally effective as dexamethasone in the treatment of oleic acid-induced acute lung injury.

The β1 Adrenergic Blocker Nebivolol Ameliorates Development of Endotoxic Acute Lung Injury

Acute lung injury (ALI) is a disease, with no effective treatment, which might result in death. Formations of excessive inflammation and oxidative stress are responsible for the pathophysiology of ALI. Nebivolol (NBL), a third-generation selective β1 adrenoceptor antagonist, has protective pharmacological properties, such as anti-inflammatory, anti-apoptotic, and antioxidant functions. Consequently, we sought to assess the efficacy of NBL on a lipopolysaccharide (LPS)-induced ALI model via intercellular adhesion molecule-1 (ICAM-1) expression and the tissue inhibitor of metalloproteinases-1 (TIMP-1)/matrix metalloproteinases-2 (MMP-2) signaling. Thirty-two rats were split into four categories: control, LPS (5 mg/kg, intraperitoneally [IP], single dose), LPS (5 mg/kg, IP, one dosage 30 min after last NBL treatment), + NBL (10 mg/kg oral gavage for three days), and NBL (10 mg/kg oral gavage for three days). Six hours after the administration of LPS, the lung tissues of the rats were removed for histopathological, biochemical, gene expression, and immunohistochemical analyses. Oxidative stress markers such as total oxidant status and oxidative stress index levels, leukocyte transendothelial migration markers such as MMP-2, TIMP-1, and ICAM-1 expressions in the case of inflammation, and caspase-3 as an apoptotic marker, significantly increased in the LPS group. NBL therapy reversed all these changes. The results of this study suggest that NBL has utility as a potential therapeutic agent to dampen inflammation in other lung and tissue injury models.

Aerosol-Administered Adelmidrol Attenuates Lung Inflammation in a Murine Model of Acute Lung Injury.

Acute lung injury (ALI) is a common and devastating clinical disorder with a high mortality rate and no specific therapy. The pathophysiology of ALI is characterized by increased alveolar/capillary permeability, lung inflammation, oxidative stress and structural damage to lung tissues, which can progress to acute respiratory distress syndrome (ARDS). Adelmidrol (ADM), an analogue of palmitoylethanolamide (PEA), is known for its anti-inflammatory and antioxidant functions, which are mainly due to down-modulating mast cells (MCs) and promoting endogenous antioxidant defense. The aim of this study is to evaluate the protective effects of ADM in a mice model of ALI, induced by intratracheal administration of lipopolysaccharide (LPS) at the dose of 5 mg/kg. ADM 2% was administered by aerosol 1 and 6 h after LPS instillation. In this study, we clearly demonstrated that ADM reduced lung damage and airway infiltration induced by LPS instillation. At the same time, ADM counteracted the increase in MC number and the expression of specific markers of MC activation, i.e., chymase and tryptase. Moreover, ADM reduced oxidative stress by upregulating antioxidant enzymes as well as modulating the Nf-kB pathway and the resulting pro-inflammatory cytokine release. These results suggest that ADM could be a potential candidate in the management of ALI.

Molecular Characterization of Kunitz-Type Protease Inhibitors from Blister Beetles (Coleoptera, Meloidae).

Protease inhibitors are widely studied since the unrestricted activity of proteases can cause extensive organ lesions. In particular, elastase activity is involved in the pathophysiology of acute lung injury, for example during SARS-CoV-2 infection, while serine proteases and thrombin-like proteases are involved in the development and/or pathology of the nervous system. Natural protease inhibitors have the advantage to be reversible and with few side effects and thus are increasingly considered as new drugs. Kunitz-type protease inhibitors (KTPIs), reported in the venom of various organisms, such as wasps, spiders, scorpions, and snakes, have been studied for their potent anticoagulant activity and widespread protease inhibitor activity. Putative KTPI anticoagulants have been identified in transcriptomic resources obtained for two blister beetle species, Lydus trimaculatus and Mylabris variabilis. The KTPIs of L. trimaculatus and M. variabilis were characterized by combined transcriptomic and bioinformatics methodologies. The full-length mRNA sequences were divided on the base of the sequence of the active sites of the putative proteins. In silico protein structure analyses of each group of translational products show the biochemical features of the active sites and the potential protease targets. Validation of these genes is the first step for considering these molecules as new drugs for use in medicine.

Immune Infiltration and N(6)-Methyladenosine ncRNA Isoform Detection in Acute Lung Injury.

Acute lung injury (ALI) is a severe form of sepsis that is associated with a high rate of morbidity and death in critically ill individuals. The emergence of ALI is the result of several factors at work. Case mortality rates might range from 40% to 70%. Researchers have discovered that epigenetic alterations are important in the pathophysiology of ALI and that using epigenetic inhibitors may help reduce symptoms. In embryonic development, circadian rhythm, the cell cycle, and cancer, methylation of m6A seems to be relevant all along the way. According to recent research, posttranscriptional methylation is a key player in the development of alveolar lymphoma. In this study, we clustered ALI based on m6A-related factors, analyzed different classes of immune cell enrichment and inflammatory cytokine expression, screened clustered differential genes for ALI to construct coexpression networks, screened key ALI genes potentially regulated by m6A modifications, and then typed the disease based on key genes to compare the consistency of different clustering results. Our findings have revealed a hitherto undiscovered prognostic sign and a therapeutic target for ALI therapy in m6A and immune invading cells, respectively.

Immunomodulation via MyD88-NFκB Signaling Pathway from Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury.

Excess inflammatory processes play a key detrimental role in the pathophysiology of acute lung injury (ALI). Mesenchymal stem cells (MSCs) were reported to be beneficial to ALI, but the underlying mechanisms have not been completely understood. The present study aimed to examine the involvement of MyD88–NFκB signaling in the immunomodulation of MSCs in mice with lipopolysaccharides (LPS)-induced ALI. We found that serum concentrations of IL-6, TNF-α, MCP-1, IL-1β, and IL-8 were significantly decreased at 6 h after LPS-induced ALI in the MSC group (p < 0.05). For each of the five cytokines, the serum concentration of each individual mouse in either group declined to a similar level at 48 h. The intensity of lung injury lessened in the MSC group, as shown by histopathology and lung injury scores (p < 0.001). The expressions of MyD88 and phospho-NFκB in the lung tissue were significantly decreased in mice receiving MSCs as measured by Western blotting and immunohistochemistry. Our data demonstrated that human umbilical cord-derived MSCs could effectively alleviate the cytokine storm in mice after LPS-induced ALI and attenuated lung injury. Firstly, we documented the correlation between the down-regulation of MyD88–NFκB signaling and immunomodulatory effects of MSCs in the situation of ALI.

The β3/5 Integrin-MMP9 Axis Regulates Pulmonary Inflammatory Response and Endothelial Leakage in Acute Lung Injury.

BackgroundAcute lung injury (ALI) is a severe respiratory disease with high rates of morbidity and mortality. Many mediators regarding endogenous or exogenous are involved in the pathophysiology of ALI. Here, we have uncovered the involvement of integrins and matrix metalloproteinases, as critical determinants of excessive inflammation and endothelial permeability, in the regulation of ALI.MethodsInflammatory cytokines were measured by quantitative real-time PCR for mRNA levels and ELISA for secretion levels. Endothelial permeability assay was detected by the passage of rhodamine B isothiocyanate-dextran. Mice lung permeability was assayed by Evans blue albumin (EBA). Western blot was used for protein level measurements. The intracellular reactive oxygen species (ROS) were evaluated using a cell-permeable probe, DCFH-DA. Intratracheal injection of lipopolysaccharide (LPS) into mice was conducted to establish the lung injury model.ResultsExogenous MMP-9 significantly aggravated the inflammatory response and permeability in mouse pulmonary microvascular endothelial cells (PMVECs) treated by LPS, whereas knockdown of MMP-9 exhibited the opposite phenotypes. Knockdown of integrin β3 or β5 in LPS-treated PMVECs significantly downregulated MMP-9 expression and decreased inflammatory response and permeability in the presence or absence of exogenous MMP-9. Additionally, the interaction of MMP-9 and integrin β5 was impaired by a ROS scavenger, which further decreased the pro-inflammatory cytokines production and endothelial leakage in PMVECs subjected to co-treatment (LPS with exogenous MMP-9). In vivo studies, exogenous MMP-9 treatment or knockdown β3 integrin significantly decreased survival in ALI mice. Notably, knockdown of β5 integrin alone had no remarkable effect on survival, but which combined with anti-MMP-9 treatment significantly improved the survival by ameliorating excessive lung inflammation and permeability in ALI mice.ConclusionThese findings support the β3/5 integrin-MMP-9 axis as an endogenous signal that could play a pivotal role in regulating inflammatory response and alveolar-capillary permeability in ALI.

Selenium-Containing Compound Ameliorates Lipopolysaccharide-Induced Acute Lung Injury via Regulating the MAPK/AP-1 Pathway.

Abstract-Acute lung injury (ALI) is characterized by a series of inflammatory reactions and serves as the main cause of mortality in intensive care unit patients. Although great progress has been made in understanding the pathophysiology of ALI, there are no effective treatments in clinic. Recently, we have synthesized a selenium-containing compound, which possesses obvious anti-inflammatory activity. The aim of the present study is to evaluate the protective effects of the selenium-containing compound 34# in LPS-induced ALI in mice as well as its underlying mechanism. Compound 34# was found to inhibit LPS-induced macrophage inflammatory cytokine release. These effects were observed to be produced via suppression of the MAPK/AP-1 pathway. Compound 34# was also noted to attenuate the LPS-induced lung inflammation in mice with ALI. The corresponding results suggested that compound 34# possesses remarkable protective effects on LPS-induced ALI. Furthermore, the MAPK/AP-1 pathway may prove to be the underlying mechanism. Accordingly, compound 34# may serve as a potential candidate for the prevention of ALI.

The protective role of prolyl oligopeptidase (POP) inhibition in acute lung injury induced by intestinal ischemia-reperfusion.

Intestinal ischemia-reperfusion (II/R) develops when the blood flow to the intestines decreases, followed by the reestablishment of the blood supply to the ischemic tissue, resulting in intestinal mucosal barrier dysfunction, with consequent severe local and systemic inflammation. Acute lung injury (ALI) represents the most serious complication after II/R. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a serine protease involved in the release of pro-angiogenic and inflammatory molecules. The aim of the present study is to assess the effects of POP-inhibition mediated by KYP-2047 treatment in the pathophysiology of ALI following II/R. An in vivo model of II/R was performed and mice were subjected to KYP-2047 treatment (intraperitoneal, 1, 2.5 and 5 mg/kg). Histological analysis, Masson’s trichrome staining, immunohistochemical, immunofluorescence, biochemical and western blots analysis were performed on ileum and lung samples. KYP-2047 treatment ameliorated histological alteration in ileum and lung, reduced collagen amount and lowered inflammatory protein levels. Moreover, TGF-β1, eNOS, VEGF and CD34 positive staining has been modulated; also, a reduction in apoptosis expression was confirmed. This research revealed the strong anti-inflammatory potential of KYP-2047 associated to its modulatory role on angiogenesis and apoptosis, suggesting POP as a novel therapeutic target for ALI after II/R.

Dysregulation of ion transport in the lung epithelium infected with SARS-CoV-2.

Dysregulation of ion transport in the lung epithelium infected with SARS-CoV-2.

MNK as a potential pharmacological target for suppressing LPS-induced acute lung injury in mice

Acute lung injury (ALI) or its more severe form, known as acute respiratory distress syndrome (ARDS), is characterized by an initial exudative phase, expression of proinflammatory mediators, activation of inflammatory leukocytes, and impairment of the lung endothelium and epithelium. Despite numerous, novel therapeutic strategies have been developed regarding the pathophysiology of ALI, current treatment is mainly supportive, as specific therapies have not been established in the past few decades. The MAP kinase-interacting kinases (MNK1 and MNK2) are serine threonine kinases which are activated by mitogen-activated protein kinases (MAPKs), regulate protein synthesis by phosphroylating eukaryotic translation initiation factor 4E (eIF4E). Although studies have shown that MAPKs pathway is involved in anti-inflammatory and preventing tissue injury processes, the role of MNKs in ALI has, until now, remained relatively unexplored. Here, we investigated whether partial inhibition of MAPKs pathway by targeting MNKs was effective in the prevention and treatment of ALI. C57BL6 mice were pretreated with MNK1 and MNK2 inhibitor (CGP57380, 30 mg/kg) for 30 min and then challenged with 5 mg/kg LPS for 6 h. The results showed that pretreatment with CGP57380 not only significantly attenuated LPS-induced lung wet/dry ratio, as well as protein content, total cells and neutrophils in bronchoalveolar lavage fluid (BALF), but also decreased the production of pro-inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) and keratinocyte-derived chemoattractant (KC). In addition, CGP57380 was observed to significantly suppress LPS-stimulated phosphorylation of eIF4E and MAPKs in the mouse bone marrow-derived macrophages (BMDMs). The involvement of MNK2 in lung injury was further evident by MNK2 knockout mice. MNK2 deficiency resulted in the attenuated lung histopathological changes, as also reflected by reductions in neutrophil counts, and the less LPS-induced the production of IL-6, TNF-α and KC in mouse BALF. Taken together, these findings demonstrated for the first time that MNK inhibition could effectively reduce the LPS-induced ALI in mice, suggesting a novel and potential application for MNK-based therapy to treat this serious disease.

Nanomedicine-Based Therapeutics to Combat Acute Lung Injury.

Acute lung injury (ALI) or its aggravated stage acute respiratory distress syndrome (ARDS) may lead to a life-threatening form of respiratory failure, resulting in high mortality of up to 30–40% in most studies. Although there have been decades of research since ALI was first described in 1967, the clinical therapeutic alternatives for ALI are still in a state of limited availability. Supportive treatment and mechanical ventilation still have priority. Despite some preclinical studies demonstrating the benefit of pharmacological interventions, none of these has been proved completely effective to date. Recent advances in nanotechnology may shed new light on the pharmacotherapy of ALI. Nanomedicine possesses targeting and synergistic therapeutic capability, thus boosting pharmaceutical efficacy and mitigating the side effects. Currently, a variety of nanomedicine with diverse frameworks and functional groups have been elaborately developed, in accordance with their lung targeting ability and the pathophysiology of ALI. The in-depth review of the current literature reveals that liposomes, polymers, inorganic materials, cell membranes, platelets, and other nanomedicine approaches have conferred attractive therapeutic benefits for ALI treatment. In this review, we explore the recent progress in the study of the nanomedicine-based therapy of ALI, presenting various nanomedical approaches, drug choices, therapeutic strategies, and outcomes, thereby providing insight into the trends.

Blocking SNHG14 Antagonizes Lipopolysaccharides-Induced Acute Lung Injury via SNHG14/miR-124-3p Axis

BackgroundEmerging evidence show that long noncoding RNAs (lncRNAs) are crucial regulators in pathophysiology of acute lung injury (ALI). Small nucleolar RNA host gene 14 (SNHG14) is a novel oncogenic lncRNA, and has been associated with inflammation-related cell injuries. Thus, we wondered the role and mechanism of SNHG14 in lipopolysaccharides (LPS)-induced ALI cell model. MethodsExpression of SNHG14, miRNA (miR)-124-3p, and transforming growth factor β type 2 receptor (TGFBR2) was detected by RT-qPCR and western blotting. Cell apoptosis was determined by methyl thiazolyl tetrazolium assay, flow cytometry, western blotting, and lactate dehydrogenase activity kit. Inflammation was measured by enzyme-linked immunosorbent assay. The interaction among SNHG14, miR-124-3p, and TGFBR2 was validated by dual-luciferase reporter assay and RNA immunoprecipitation. ResultsLPS administration attenuated human lung epithelial cell viability and B-cell lymphoma-2 expression, but augmented apoptosis rate, cleaved-caspase-3 expression, lactate dehydrogenase activity, and secretions of tumor necrosis factor-α, interleukin-1β, and IL-6 in A549 cells. Thus, LPS induced A549 cells apoptosis and inflammation, wherein SNHG14 was upregulated and miR-124-3p was downregulated. However, silencing SNHG14 could suppress LPS-induced apoptosis and inflammation depending on upregulating miR-124-3p via target binding. Similarly, overexpressing miR-124-3p attenuated LPS-induced A549 cells injury through inhibiting its downstream target TGFBR2. Furthermore, SNHG14 knockdown could also affect TGFBR2 expression via miR-124-3p. ConclusionsSNHG14 knockdown prevents A549 cells from LPS-induced apoptosis and inflammation through regulating miR-124-3p and TGFBR2, suggesting a novel SNHG14/miR-124-3p/TGFBR2 circuit in alveolar epithelial cells on the set of ALI.

Inhalational versus intravenous anesthetics during one lung ventilation in elective thoracic surgeries: A narrative review.

The anesthesia regimen used during one lung ventilation (OLV) carry the potential to affect intra-operative course and post-operative outcomes, by its effects on pulmonary vasculature and alveolar inflammation. This narrative review aims to understand the pathophysiology of acute lung injury during one lung ventilation, and to study the effects of inhalational versus intravenous anaesthetics on intraoperative and post-operative outcomes, following thoracic surgery. For this purpose, we independently searched 'PubMed', 'Google Scholar' and 'Cochrane Central' databases to find out randomized controlled trials (RCTs), in English language, which compared the effects of intravenous versus inhalational anaesthetics on intraoperative and post-operative outcomes, in elective thoracic surgeries, in human beings. In total, 38 RCTs were included in this review. Salient results of the review are- Propofol reduced intraoperative shunt and maintained better intraoperative oxygenation than inhalational agents. However, use of modern inhalational anaesthetics during OLV reduced alveolar inflammation significantly, as compared to propofol. Regarding post-operative complications, the evidence is not conclusive enough but slightly in favour of inhalational anaesthetics. Thus, we conclude that modern inhalational anaesthetics, by their virtue of better anti-inflammatory properties, exhibit lung protective effects and hence, seem to be safe for maintenance of anesthesia during OLV in elective thoracic surgeries. Further research is required to establish the safety of these agents with respect to long term post-operative outcomes like cancer recurrence.

Experimental Models of Acute Lung Injury: their Advantages and Limitations

Abstract Acute damage to the lung may originate from various direct and indirect reasons. Direct lung injury may be caused by pneumonia, near-drowning, aspiration, inhalation of toxic gases etc., while indirect lung injury is secondary, following any severe extra-pulmonary disease, e.g. sepsis, acute pancreatitis, or severe trauma. Due to a complex pathophysiology of the acute lung injury, the treatment is also extremely complicated and except for lung-protective ventilation there have been no specific treatment approaches recommended. An urgent need for a reliable and sufficiently effective treatment forces the researchers into testing novel therapeutic strategies. However, most of these determinations should be done in the laboratory conditions using animals. Complex methods of preparation of various experimental models of the acute lung injury has gradually developed within decades. Nowadays, there have been the models of direct, indirect, or mixed lung injury well established, as well as the models evoked by a combination of two triggering factors. Although the applicability of the results from animal experiments to patients might be limited by many factors, animal models are essential for understanding the patho-physiology of acute lung injury and provide an exceptional opportunity to search for novel therapeutical strategies.

Mesenchymal stem cells alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of Ly6C+ CD8+ T cells

Systemic inflammatory processes, including alveolar injury, cytokine induction, and neutrophil accumulation, play key roles in the pathophysiology of acute lung injury (ALI). The immunomodulatory effects of mesenchymal stem cells (MSCs) can contribute to the treatment of inflammatory disorders. In previous studies, the focus was on innate immune cells and the effects of MSCs on ALI through CD8+ T cells remain unclear. In the present study, lipopolysaccharide (LPS) was used to induce ALI in mice. ALI mice were treated with MSCs via intratracheal instillation. Survival rate, histopathological changes, protein levels, total cell count, cytokine levels, and chemokine levels in alveolar lavage fluid were used to determine the efficacy of MSCs. Mass cytometry and single-cell RNA sequencing (scRNA-seq) were used to characterize the CD8+ T cells in the lungs. Ly6C− CD8+ T cells are prevalent in normal mice, whereas a specialized effector phenotype expressing a high level of Ly6C is predominant in advanced disease. MSCs significantly mitigated ALI and improved survival. MSCs decreased the infiltration of CD8+ T cells, especially Ly6C+ CD8+ T cells into the lungs. Mass cytometry revealed that CD8+ T cells expressing high Ly6C and CXCR3 levels caused tissue damage in the lungs of ALI mice, which was alleviated by MSCs. The scRNA-seq showed that Ly6C+ CD8+ T cells exhibited a more activated phenotype and decreased expression of proinflammatory factors that were enriched the most in immune chemotaxis after treatment with MSCs. We showed that CD8+ T cells play an important role in MSC-mediated ALI remission, and both infiltration quantity and proinflammatory function were inhibited by MSCs, indicating a potential mechanism for therapeutic intervention.