Mechanisms Of Acute Lung Injury Research Articles

Desflurane alleviates LPS-induced acute lung injury by modulating let-7b-5p/HOXA9 axis.

Acute lung injury (ALI) is characterized by acute respiratory failure with tachypnea and widespread alveolar infiltrates, badly affecting patients' health. Desflurane (Des) is effective against lung injury. However, its mechanism in ALI remains unknown. BEAS-2B cells were incubated with lipopolysaccharide (LPS) to construct an ALI cell model. Cell apoptosis was evaluated using flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was employed to examine the levels of inflammatory cytokines. Interactions among let-7b-5p, homeobox A9 (HOXA9), and suppressor of cytokine signaling 2 (SOCS2) were verified using Dual luciferase activity, chromatin immunoprecipitation (ChIP), and RNA pull-down analysis. All experimental data of this study were derived from three repeated experiments. Des treatment improved LPS-induced cell viability, reduced inflammatory cytokine (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6)) levels, decreased cell apoptosis, down-regulated the pro-apoptotic proteins (Bcl-2-associated X protein (Bax) and cleaved caspase 3) expression, and up-regulated the anti-apoptotic protein B-cell-lymphoma-2 (Bcl-2) expression in LPS-induced BEAS-2B cells. Des treatment down-regulated let-7b-5p expression in LPS-induced BEAS-2B cells. Moreover, let-7b-5p inhibition improved LPS-induced cell injury. let-7b-5p overexpression weakened the protective effects of Des. Mechanically, let-7b-5p could negatively modulate HOXA9 expression. Furthermore, HOXA9 inhibited the NF-κB signaling by enhancing SOCS2 transcription. HOXA9 overexpression weakened the promotion of let-7b-5p mimics in LPS-induced cell injury. Des alleviated LPS-induced ALI via regulating let-7b-5p/ HOXA9/NF-κB axis.

Urolithin A exerts a protective effect on lipopolysaccharide-induced acute lung injury by regulating HMGB1-mediated MAPK and NF-κB signaling pathways.

Acute lung injury (ALI) is a severe inflammatory disorder that has a high morbidity and mortality rate. Urolithin A (UA) is reported to have anti-inflammatory and anti-oxidative effects in ALI. However, its molecular mechanisms in ALI remain to be explored. Mice and BEAS-2B cells were administrated with lipopolysaccharide (LPS) to mimic the ALI model in vivo and in vitro. Hematoxylin-eosin (HE) staining was used to detect the pathological injury of lung tissues. The levels of proinflammatory cytokines in bronchoalveolar lavage fluid (BALF) and culture supernatant and the levels of oxidative stress markers in lung tissues were measured using ELISA. DCFH-DA probe was used to assess the reactive oxygen species (ROS) level. TUNEL staining and flow cytometry were performed to determine cell apoptosis. The key targets and pathways were confirmed by immunohistochemistry (IHC) and western blot. UA suppressed the pathologic damage, wet/dry weight ratio, and total protein and inflammatory cells in BALF. UA decreased neutrophil infiltration and proinflammatory cytokines production. UA reduced the level of malondialdehyde (MDA) and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in pulmonary tissues. UA also inhibited cell apoptosis in lung tissues by decreasing Bax expression and increasing Bcl-2 expression. In addition, UA suppressed LPS-induced inflammatory factor production, ROS level, and cell apoptosis in BEAS-2B. Importantly, UA decreased the expression of HMGB1 in LPS-treated mice and BEAS-2B cells. HMGB1 overexpression greatly abrogated the inhibition of UA on inflammation, ROS, and cell apoptosis in LPS-administrated BEAS-2B. Furthermore, UA treatment suppressed the phosphorylated levels of p38, JNK, ERK, and p65 in LPS-administrated mice and BEAS-2B cells. UA alleviated lung inflammation, oxidative stress, and apoptosis in ALI by targeting HMGB1 to inactivate the MAPK/NF-κB signaling, suggesting the potential of UA to treat ALI.

Kaempferitrin alleviates LPS-induced septic acute lung injury in mice through downregulating NF-κB pathway.

Acute lung injury (ALI) causes severe and uncontrolled pulmonary inflammation and has high morbidity in dying patients. This study aimed to evaluate the potential function of Kaempferitrin (Kae) and uncover its mechanisms in ALI. We evaluated the role of Kae in ALI through the lipopolysaccharide (LPS)-induced histopathological changes, lung wet/dry (W/D) ratio, total bronchoalveolar lavage fluid (BALF) cells count, pulmonary inflammation, and the levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-1β. The effect of Kae on NF-κB signaling pathway was discovered through the protein expression levels of transcription factors p65, p-p65, IκBα, and p-IκBα by Western blot analysis. The results showed that Kae could improve lung injury by reducing apoptosis, histopathological changes, and lung W/D ratio; more importantly, Kae enhanced the survival of ALI mice. Moreover, Kae relieved inflammation, as it reduced total BALF cells count, and deceased the levels of TNF-α, IL-6, and IL-1β in serum. In addition, Western blot analysis data suggested that Kae could decrease the protein expression levels of transcription factors p65, p-p65, IκB-α, and p-IκB-α, which were promoted by LPS. The results of this study suggested that Kae could relieve LPS-induced ALI in mice and reduce inflammation and apoptosis through NF-κB pathway.

Monocyte-derived exosomal XIST exacerbates acute lung injury by regulating the miR-448-5p/HMGB2 axis.

Monocyte-derived exosomes (Exos) have been implicated in inflammation-related autoimmune/inflammatory diseases via transferring bioactive cargoes to recipient cells. The purpose of this study was to investigate the possible effect of monocyte-derived Exos on the initiation and the development of acute lung injury (ALI) by delivering long non-coding RNA XIST. Key factors and regulatory mechanisms in ALI were predicted by bioinformatics methods. BALB/c mice were treated with lipopolysaccharide (LPS) to establish an ALI in vivo model and then injected with Exos isolated from monocytes transduced with sh-XIST to evaluate the effect of monocyte-derived exosomal XIST on ALI. HBE1 cells were co-cultured with Exos isolated from monocytes transduced with sh-XIST for further exploration of its effect. Luciferase reporter, RIP and RNA pull-down assays were performed to verify the interaction between miR-448-5p and XIST, miR-448-5p and HMGB2. miR-448-5p was significantly poorly expressed while XIST and HMGB2 were highly expressed in the LPS-induced mouse model of ALI. Monocyte-derived Exos transferred XIST into HBE1 cells where XIST competitively inhibited miR-448-5p and reduced the binding of miR-448-5p to HMGB2, thus upregulating the expression of HMGB2. Furthermore, in vivo data revealed that XIST delivered by monocyte-derived Exos downregulated miR-448-5p expression and up-regulated HMGB2 expression, ultimately contributing to ALI in mice. Overall, our results indicate that XIST delivered by monocyte-derived Exos aggravates ALI via regulating the miR-448-5p/HMGB2 signaling axis.

Keratin7 and Desmoplakin are involved in acute lung injury induced by sepsis through RAGE

Keratin 7 (Krt7) is a member of the keratin family and is primarily involved in cytoskeleton composition. It has been shown that Krt7 is able to influence its own remodeling and interactions with other signaling molecules via phosphorylation at specific sites unique to Krt7. However, its molecular mechanism in acute lung injury (ALI) remains unclear. In this study, differential proteomics was used to analyze lung samples from the receptor for advanced glycation end products (RAGE)-deficient and (wild-type)WT-septic mice. We screened for the target protein Krt7 and identified Ser53 as the phosphorylation site using mass spectrometry (MS), and this phosphorylation further triggered the deformation and disintegration of Desmoplakin (Dsp), ultimately leading to epithelial barrier dysfunction. Furthermore, we demonstrated that in sepsis, mDia1/Cdc42/p38 MAPK signaling activation plays a role in septic lung injury. We also explored the mechanism of alveolar dysfunction of the Krt7-Dsp complex in the epithelial cell barrier. In summary, the present findings increase our understanding of the pathogenesis of septic acute lung injury.

Toxicologic pathological mechanism of acute lung injury induced by oral administration of benzalkonium chloride in mice.

Benzalkonium chloride (BAC) intoxication causes fatal lung injuries, such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the pathogenesis of ALI/ARDS induced by BAC ingestion is poorly understood. This study aimed to clarify the mechanism of lung toxicity after BAC ingestion in a mouse model. BAC was orally administered to C57BL/6 mice at doses of 100, 250, and 1250mg/kg. After administration, BAC concentrations in the blood and lungs were evaluated via liquid chromatography with tandem mass spectrometry. Lung tissue injury was evaluated via histological and protein analyses. Blood and lung BAC concentration levels after oral administration increased in a dose-dependent manner, with the concentrations directly proportional to the dose administered. The severity of lung injury worsened over time after the oral administration of 1250mg/kg BAC. An increase in the terminal transferase dUTP nick end labeling-positive cells and cleaved caspase-3 levels was observed in the lungs after 1250mg/kg BAC administration. In addition, increased cleaved caspase-9 levels and mitochondrial cytochrome c release into the cytosol were observed. These results suggest that lung tissue injury with excessive apoptosis contributes to BAC-induced ALI development and exacerbation. Our findings provide useful information for developing an effective treatment for ALI/ARDS induced by BAC ingestion.

Inhalation of an RNA aptamer that selectively binds extracellular histones protects from acute lung injury

Acute lung injury (ALI) is a syndrome of acute inflammation, barrier disruption, and hypoxemic respiratory failure associated with high morbidity and mortality. Diverse conditions lead to ALI, including inhalation of toxic substances, aspiration of gastric contents, infection, and trauma. A shared mechanism of acute lung injury is cellular toxicity from damage-associated molecular patterns (DAMPs), including extracellular histones. We recently described the selection and efficacy of a histone-binding RNA aptamer (HBA7). The current study aimed to identify the effects of extracellular histones in the lung and determine if HBA7 protected mice from ALI. Histone proteins decreased metabolic activity, induced apoptosis, promoted proinflammatory cytokine production, and caused endothelial dysfunction and platelet activation invitro. HBA7 prevented these effects. The oropharyngeal aspiration of histone proteins increased neutrophil and albumin levels in bronchoalveolar lavage fluid (BALF) and precipitated neutrophil infiltration, interstitial edema, and barrier disruption in alveoli in mice. Similarly, inhaling wood smoke particulate matter, as a clinically relevant model, increased lung inflammation and alveolar permeability. Treatment by HBA7 alleviated lung injury in both models of ALI. These findings demonstrate the pulmonary delivery of HBA7 as a nucleic acid-based therapeutic for ALI.

Overexpression of IFIT1 protects against LPS-induced acute lung injury via regulating CCL5-p65NF-κB signaling.

Acute lung injury (ALI) is featured by intensive inflammatory responses causing significant morbidity and mortality. Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), induced by interferon (IFN), has been discovered to modulate viral infection and cell apoptosis and inhibit the production of pro-inflammatory cytokines. However, it's role and mechanism in ALI remain unclear and need to be explored furtherly. Here, we discovered that IFIT1 decreased the expression of TNF-α, IL-1β and IL-6 in mouse-derived macrophage cells (MH-S) and alleviated apoptosis of murine lung epithelial cells (MLE-12) induced by MH-S cell supernatant, contributing to anti-inflammatory and antiapoptotic effects in vitro and in vivo. Moreover, RNA sequencing analysis (RNA-seq) showed that inflammatory chemokine CC motif chemokine ligand 5 (CCL5) partially eliminated the protective effects of IFIT1 and promoted the expression of inflammatory cytokines TNF-α, IL-1β and IL-6 by CCL5-p65NF-κB signaling pathway. This study demonstrated that IFIT1 attenuated ALI-associated inflammation and cell apoptosis by regulating the CCL5-p65NF-κB signaling pathway. These findings are of great significance for the treatment of lung injury.

Down-regulation of KLF9 ameliorates LPS-caused acute lung injury and inflammation in mice via reducing GSDMD expression

Acute lung injury (ALI) is considered as a severe respiratory disease with aggravated inflammatory responses. Krüppel-like factor 9 (KLF9), a member of KLF family, has been reported to be involved in inflammatory disorders. However, the effect of KLF9 in ALI has not been elucidated. Here the present study was to clarify the role of KLF9 and its mechanism in ALI. The ALI in vitro model was established with lipopolysaccharide (LPS)-treated RAW264.7 cells. Mice were injected with LPS to conduct an ALI in vivo model. The expression of KLF9 and gasdermin D (GSDMD) was examined using quantitative reverse transcription-PCR, haematoxylin-eosin/immunohistochemistry staining and western blot assays. Enzyme-linked immunosorbent assay was employed to detect the levels of inflammatory cytokines. JASPAR database was used to predict the recognition motif of KLF9, and the relationship between KLF9 and GSDMD was determined by luciferase reporter assay and chromatin immunoprecipitation analysis. The number of neutrophils in bronchoalveolar lavage fluid as well as the wet/dry weight ratio was caculated. The results showed that The expression of KLF9 in lung was significantly increased in LPS-stimulated mice. Moreover, KLF9 knockout relieved the lung injury in ALI mice. GSDMD is one of targets genes of the transcription factor KLF9. KLF9 knockout induced a decreased expression of GSDMD in LPS-treated mice. Furthermore, in RAW264.7 cells after LPS administration, KLF9 knockdown reduced the levels of inflammatory factors and suppressed the expression of GSDMD. In summarise, these findings exhibited that KLF9 knockout could mitigate the lung injury and inflammatory responses in ALI mice by directly regulating GSDMD.

MicroRNA-130b-3p delivery by mesenchymal stem cells-derived exosomes confers protection on acute lung injury

Objective Researchers have investigated miR-130b-3p in lung disease pathology, such as lung fibrosis. The present study was performed to elucidate the miR-130b-3p-involved mechanism in acute lung injury (ALI) through delivery by mesenchymal stem cells-derived exosomes (MSCs-Exo). Methods ALI mouse models were induced via intratracheal administration of lipopolysaccharide (LPS) and treated with MSCs-Exo. Lung dry-wet (W/D) ratio, inflammatory factors in the bronchoalveolar lavage fluid, pathological damage and apoptosis in the lung tissues were analyzed. Expression levels of miR-130b-3p and TGFBR1 were measured in the mouse lung tissues, and the interaction between miR-130b-3p and TGFBR1 was studied. Results MSCs-Exo relieved LPS-induced ALI in mice by reducing lung W/D ratio and inflammatory response, and attenuating lung tissue pathological damage and reducing the alveolar cell apoptosis. miR-130b-3p delivery by MSCs-Exo reduced LPS-induced ALI in mice. TGFBR1 was determined to be a downstream target gene of miR-130b-3p. Inhibition of TGFBR1 could remit LPS-induced ALI in mice. The protection mediated by MSCs-Exo carrying miR-130b-3p could be rescued by elevating TGFBR1 expression. Conclusion miR-130b-3p delivery by MSCs-Exo confers protection on ALI in mice via the downregulation of TGFBR1.

The circular RNA hsa_circ_0003091 regulates sepsis-induced lung injury by sponging the miR-149/Smad2 axis.

Sepsis-induced acute lung injury (ALI) is a severe cause of death. Increasing evidence has identified circular RNAs (circRNAs) acting as critical regulators of human diseases. However, their expression pattern and underlying mechanisms in ALI remain unclear. Herein, we screened the circRNAs of ALI patients and constructed a lung injury murine model using lipopolysaccharides (LPS) induction. Functional analyses of targeted circRNA were performed in vivo and in vitro. Then, the downstream miRNA and mRNA of specific circRNAs were identified. Compared to healthy subjects, 35 circRNAs were upregulated and 9 circRNAs were downregulated in sepsis patients. The top 10 differentially expressed circRNAs were selected for validation and has_circ_0003091 was selected. The ALI mice presented significantly elevated has_circ_0003091 (mmu_circ_0015268). The functional analysis revealed that mmu_circ_0015268 contributed to the pulmonary injury, cell apoptosis, inflammatory responses, and endothelial activation in the ALI murine model. On the other hand, silencing mmu_circ_0015268 showed protective effects in LPS-treated mice and PMVECs. Furthermore, mmu_circ_0015268 sponged miR-149 to upregulate the expression of its target Smad2. In summary, we demonstrated that has_circ_0003091 might be a novel target for the management and treatment of sepsis-induced ALI.

The Reaction Pathway of miR-30c-5p Activates Lipopolysaccharide Promoting the Course of Traumatic and Hemorrhagic Shock Acute Lung Injury.

Acute lung injury (ALI) is an acute hypoxic respiratory failure caused by diffuse inflammatory injury in alveolar epithelial cells during severe infection, trauma, and shock. Among them, trauma/hemorrhagic shock (T/HS) is the main type of indirect lung injury. Despite a great number of clinical studies, indirect factor trauma/hemorrhagic shock to the function and the mechanism in acute lung injury is not clear yet. Therefore, it is still necessary to carry on relevant analysis in order to thoroughly explore its molecular and cellular mechanisms and the pathway of disease function. In our research, we aimed to identify potential pathogenic genes and do modular analysis by downloading disease-related gene expression profile data. And our dataset is from the NCBI-GEO database. Then, we used the Clusterprofiler R package, GO function, and KEGG pathway enrichment analysis to analyze the core module genes. In addition, we also identified key transcription factors and noncoding RNAs. Based on the high degree of interaction of potential pathogenic genes and their involved functions and pathways, we identified 17 dysfunction modules. Among them, up to 9 modules significantly regulate the response to bacterial-derived molecules, and the response to lipopolysaccharide and other related functional pathways that mediate disease development. In addition, miR-290, miR-30c-5p, miR-195-5p, and miR-1-3p-based ncRNA and Jun, Atf1, and Atf3-based transcription factors have a total of 80 transcription drivers for functional modules. In summary, this study confirmed that miR-30c-5p activates lipopolysaccharide response pathway to promote the pathogenesis of ALI induced by hemorrhagic shock. This result can be an important direction for further research on related deepening diseases such as acute respiratory distress syndrome (ARDS). It further provides a piece of scientific medical evidence for revealing the pathogenic principle and cure difficulty of acute lung injury and also provides important guidance for the design of therapeutic strategies and drug development.

Long noncoding RNA Kcnq1ot1 prompts lipopolysaccharide-induced acute lung injury by microRNA-7a-5p/Rtn3 axis

BackgroundLong noncoding RNA (lncRNA)-regulated mechanism in acute lung injury (ALI) has attracted special interests in study researches. We planned to disclose whether KCNQ1 overlapping transcript 1 (Kcnq1ot1) is involved in ALI and its mechanism.MethodsThe lipopolysaccharide (LPS)-induced ALI model was established in mice. Kcnq1ot1, microRNA (miR)-7a-5p and Reticulon 3 (Rtn3) levels were measured in lung tissues of mice. The vector that changed Kcnq1ot1, miR-7a-5p and Rtn3 expression was injected into LPS-treated mice, and pathological damage, fibrosis, apoptosis and inflammatory response were subsequently examined in lung tissues. The relation between Kcnq1ot1 and miR-7a-5p, and that between miR-7a-5p and Rtn3 were identified.ResultsKcnq1ot1 and Rtn3 expression increased while miR-7a-5p expression decreased in LPS-treated mice. Reduced Kcnq1ot1 or elevated miR-7a-5p alleviated pathological damage, fibrosis, apoptosis and inflammatory response in ALI mice, while overexpressed Rtn3 worsened ALI in mice. Downregulation of Rtn3 reversed the exacerbation of miR-7a-5p downregulation in ALI mice. Kcnq1ot1 competitively bound to miR-7a-5p and miR-7a-5p negatively mediated Rtn3 expression.ConclusionOur experiments evidence that silencing Kcnq1ot1 upregulates miR-7a-5p to suppress Rtn3 expression, thereby diminishing LPS-induced ALI.

Short term protective effect of digitoxin in sepsis-induced acute lung injury

Purpose: Digitoxin is a cardiac glycoside used in the treatment of heart failure. Inspired by its known anti-inflammatory effect, this study aims to investigate the effect of digoxin in a sepsis model and to bring to light its effect and underlying mechanism in acute lung injury (ALI). Method: 28 wistar albino rats were divided into 4 groups. Sepsis model is performed by the feces intraperitoneal-injection procedure (FIP). Results: TNF-a, CRP, IL-6, IL 1-Beta, lactic acid, and MDA values were significantly decreased in the FIP+digitoxin group compared to the FIP+Saline group. When the same groups were examined, histological improvements such as decrease in alveolar inflammation and decrease in septal thickening in the digitoxin group and thorax CT were found to be significantly higher in the Hounsfield unit digitoxin group compared to the Saline group. Conclusion: Digitoxin has shown biochemical improvement in sepsis with all known mechanisms of action, and healing effects in both computerized tomography and histology in the lung.

Study on the Efficacy and Safety of Ambroxol Combined with Methylprednisolone in Patients with Acute Lung Injury.

Background There is no better treatment method towards paraquat-induced acute lung injury (ALI) at present. Ambroxol combined with methylprednisolone exhibits a significant improvement effect on ALI treatment, whereas their mechanism in ALI is still unclear. Methods 64 patients with ALI caused by paraquat poisoning brought to our hospital from January 2015 to January 2018 were selected. They were separated into a combined treatment group (CTG) and a routine treatment group (RTG) on the basis of different treatment methods. The survival of patients was observed after 7 days of treatment. Arterial blood gas, oxygen partial pressure (PaO2), partial pressure of carbon dioxide (PaCO2), oxygenation index (PaO2/FiO2), patient's spontaneous respiratory rate (RR), tidal volume (VT), and positive end-expiratory pressure (PEEP) were observed before and after treatment for 7 days. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were analyzed. The differences of indexes between the dead patients and the survivors were observed, and the potential predictive value of death was analyzed. Results After treatment, the indexes of patients were significantly improved in both groups compared with those before therapy. Further comparison showed that the improvement of PaO2, PaCO2, and PaO2/FiO2 in CTG was obviously higher than that in RTG (p < 0.05). The improvement of RR, PEEP, and VT in CTG was obviously higher than that in RTG (p < 0.05). The decreased degree of IL-6 and TNF-α in CTG was higher than that in RTG (p < 0.05). The 7-day mortality rate of 64 patients was 39.06%, and there was no obvious difference in the 7-day survival rate in both groups (p = 0.649). IL-6 and TNF-α were expected to be potential prediction indexes of paraquat-induced ALI. Conclusion Ambroxol combined with methylprednisolone significantly improved the oxygen partial pressure and oxygenation index of patients with paraquat-induced ALI and inhibited the inflammatory response of patients.

BMI1 silencing increases mitochondrial damage in Hyperoxia‐induced Acute Lung Injury (HALI) in vivo and invitro models

Acute Lung Injury (ALI), is a conjunction of signs and symptoms that leads to acute hypoxemic respiratory failure with bilateral pulmonary infiltrates not attributed to cardiogenic origin and decreases in the availability of gas exchange. It is caused by a massive innate immune response, with migration of white blood cells (neutrophils and macrophages principally) and cytokines storm, followed by alterations in mitochondrial function, increase in reactive oxygen species production, and oxidative stress that in turn induces more mitochondrial damage. Several studies have shown that mitochondrial alterations are key events in the mechanism of ALI and reduce mitochondrial dysfunction could be possible target in the treatment of the disease. Some authors have determined that BMI1 has a role in mitochondrial function, but its role is unclear, and the metabolic pathway through which BMI1 regulates mitochondrial function and oxidative stress has not been established. Our study shows that BMI1 plays a pivotal role in mitochondrial function during HALI in vitro and in vivo, and BMI1 silencing or depletion induces mitophagy and reduces cell survival by blocking PI3K pathway mediated by PTEN increases, deteriorates the availability of lung cells to produce ATP and to consume of oxygen recurring to glycolysis. In vivo the depletion of BMI1 decrease the lung compliance and elastance inducing deleterious lung damage in mice, which can lead to worsening of HALI. Our research show BMI1 as a therapeutic target in the treatment of ALI/ARDS.

NaHS Alleviated Cell Apoptosis and Mitochondrial Dysfunction in Remote Lung Tissue after Renal Ischemia and Reperfusion via Nrf2 Activation-Mediated NLRP3 Pathway Inhibition.

Objective Acute kidney injury (AKI) is a common and severe complication in critically ill patients, often caused by renal ischemia-reperfusion (RIR). Previous studies have confirmed that lung injury, rather than renal injury, is one of the leading causes of AKI-induced death. The pathophysiological mechanisms of acute lung injury (ALI) resulting from AKI are very complex and remain unclear. In the present study, we aimed to explore the protective effects and potential mechanism of sodium hydrosulfide (NaHS) on lung injury in RIR mice. Methods The RIR model was established in wild-type and Nrf2−/− mice. Different groups of mice were treated with NaHS and MCC950. Lung tissues were harvested to detect lung injury, mitochondrial function, cell apoptosis, the NLRP3 inflammasome, and Nrf2 pathway-related molecules. Results RIR led to a deterioration in lung histology, the wet/dry weight ratio, PaO2/FiO2, and mitochondrial function, in addition to stimulating the activation of the NLRP3 and Nrf2 pathways. MCC950 alleviated mitochondrial dysfunction, lung apoptosis, and histology injury in the lungs after RIR. NaHS treatment markedly improved the lung histological scores, the wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) cell counts, BALF neutrophil counts, BALF neutrophil elastase activity, BALF protein concentration, PaO2/FiO2, mitochondrial morphology, the red/green fluorescence intensity that indicates changes in mitochondrial membrane potential, respiratory control rate (RCR), ATP, reactive oxygen species (ROS) release, and cell apoptosis via Nrf2-mediated NLRP3 pathway inhibition. Conclusion NaHS protected against RIR-induced lung injury, mitochondrial dysfunction, and inflammation, which is associated with Nrf2 activation-mediated NLRP3 pathway inhibition.

HYPERTENSION AND COVID-19: THE POSSIBLE ROLE OF METALLOPROTEINASE-9 IN COVID-19 PATHOPHYSIOLOGY

Objective: The pathophysiological mechanism of acute lung injury in COVID-19 includes a cascade of local and systemic responses with activation of several pro-inflammatory cytokines, including metalloproteinases. The aim of this study is investigate the role of matrix metalloproteinase-9 (MMP-9) in plasma from patients with severe COVID-19 hospitalized in a Brazilian ICU. Design and method: The study was designed to analyze the MMP-9 plasmatic in COVID-19 severe infection. Epidemiological data and blood samples were obtained from 42 subjects hospitalized in the ICU with clinically SARS-CoV-2 infection confirmed by RT-PCR (COVID), and 15 healthy subjects (Control). Zymography methods obtained the MMP-9 plasma activity. Continuous variables are shown by mean ± STDV and analyzed by the Mann-Whitney test. Categorical variables were compared by the Chi-squared test. The MMMP-9 activity is shown in the log of normalized and analyzed by unpaired T-test. Two-way ANOVA was used to analyze subgroups divided by gender, age greater or less than the median 60.4-year-old, hypertensive or normotensive, non-obese or obese. Results: The COVID and Control groups did not differ significantly by age (62.6 ± 13vs.57.6 ± 12.2 years old, p = 0.097) and BMI (30.3 ± 6.1vs.29.33 ± 5.7 kg/m2, p = 0.338). The COVID group has fewer women than the Control group (28.6%vs.80%, p = 0.0008). The COVID subjects with hypertension were 42% vs.67% in the Control group (p = 0,2), and diabetes was similar in both groups. The hospital stay in the COVID group was 14.5 ± 11.5 days and the hospitalization death rate was 32.5%. The COVID-19 group has shown an increase in MMP-9 activity compared with the Control group (0.38 ± 0.072 UA; 95%CI = 0.23–0.52,p &lt; 0.0001). The MMP-9 activity increasing was independent of gender (p = 0.45), age (p = 0.93), BMI (p = 0.3) or hypertension (p = 0.6) and dependent of the COVID-19 infection (p &lt; 0.0001). Therefore, our data are showing that the COVID-19 infection was responsible for MMP-9 improvement in plasma of severe COVID-19 infection (p &lt; 0.0001) while all different analyses consistently showed a significant effect of COVID-19 infection (p &lt; 0.0001). Conclusions: There is a significant increase in the MMP-9 plasmatic activity in severe COVID-19 patients independently of sex, age, obesity, and hypertension. Therefore, MMP-9 may be a potential new target for acute lung injury therapy in patients with COVID-19.

A bibliometric analysis of acute respiratory distress syndrome (ARDS) research from 2010 to 2019.

Thousands of papers on acute respiratory distress syndrome (ARDS) have been published in the last decade. This study aimed to evaluate the research hotspots and future trends in ARDS research using bibliometric analysis. All relevant literature on ARDS published between 2010 and 2019 was retrieved from the Web of Science Core Collection database, and the retrieval strategy was TS = (ARDS OR acute respiratory distress syndrome). Bibliometric analysis was conducted using VOSviewer and the online bibliometric analysis platform based on retrieved data. Bibliographic Item Co-occurrence Matrix Builder (BICOMB) and gCLUTO software were used to evaluate and visualize the results, and to explore the hotspots in the field of ARDS. A total of 9,858 ARDS research articles dated between 2010 and 2019 were included. The dominant position of the United States in global ARDS research throughout this 10-year period was evident, and it was also the country most frequently involved in international cooperation. The University of Toronto was the most productive institution and a leader in research collaboration. Critical Care Medicine was the most productive journal in terms of the number of publications on ARDS. Further, Matthay MA, Pelosi P, Slutsky AS, and Thompson BT all made significant contributions to ARDS research. A total of 37 most frequent keywords were identified and belonged to 5 hotspots: (I) adult and pediatric ARDS; (II) life-support monitoring parameters and therapy in severe patients with ARDS; (III) molecular mechanisms of acute lung injury; (IV) influenza-related pneumonia; and (V) severe complications of ARDS. Also, in the last 5 years, the keywords "biomarkers", "pathway", "NF-κB", "epidemiology", "life-support", and "ECMO" began to appear in the ARDS research field. In the decade from 2010 to 2019, the United States was a global leader in ARDS research, and hotspots included epidemiology, mechanisms, monitoring parameters, and therapy, especially mechanical ventilation. Our results suggest that the mechanisms of ARDS and novel life-support therapies will remain research hotspots in the future. International collaboration is also expected to widen and deepen in the field of ARDS research.

Validation of novel hub genes and molecular mechanisms in acute lung injury using an integrative bioinformatics approach.

Acute lung injury (ALI) is an inflammatory pulmonary disease that can easily develop into serious acute respiratory distress syndrome, which has high morbidity and mortality. However, the molecular mechanism of ALI remains unclear, and few molecular biomarkers for diagnosis and treatment have been identified. In this study, we aimed to identify novel molecular biomarkers using a bioinformatics approach. Gene expression data were obtained from the Gene Expression Omnibus database, co-expressed differentially expressed genes (CoDEGs) were identified using R software, and further functional enrichment analyses were conducted using the online tool Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction network was established using the STRING database and Cytoscape software. Lipopolysaccharide (LPS)-induced ALI mouse model was constructed and verified. The hub genes were screened and validated in vivo. The transcription factors (TFs) and miRNAs associated with the hub genes were predicted using the NetworkAnalyst database. In total, 71 CoDEGs were screened and found to be mainly involved in the cytokine-cytokine receptor interactions, and the tumor necrosis factor and malaria signaling pathways. Animal experiments showed that the lung injury score, bronchoalveolar lavage fluid protein concentration, and wet-to-dry weight ratio were higher in the LPS group than those in the control group. Real-time polymerase chain reaction analysis indicated that most of the hub genes such as colony-stimulating factor 2 (Csf2) were overexpressed in the LPS group. A total of 20 TFs including nuclear respiratory factor 1 (NRF1) and two miRNAs were predicted to be regulators of the hub genes. In summary, Csf2 may serve as a novel diagnostic and therapeutic target for ALI. NRF1 and mmu-mir-122-5p may be key regulators in the development of ALI.