Induced Lung Injury Research Articles

Fine particulate matter aggravates smoking induced lung injury via NLRP3/caspase-1 pathway in COPD

BackgroundExposure to noxious particles, including cigarette smoke and fine particulate matter (PM2.5), is a risk factor for chronic obstructive pulmonary disease (COPD) and promotes inflammation and cell death in the lungs. We investigated the combined effects of cigarette smoking and PM2.5 exposure in patients with COPD, mice, and human bronchial epithelial cells.MethodsThe relationship between PM2.5 exposure and clinical parameters was investigated in patients with COPD based on smoking status. Alveolar destruction, inflammatory cell infiltration, and pro-inflammatory cytokines were monitored in the smoking-exposed emphysema mouse model. To investigate the mechanisms, cell viability and death and pyroptosis-related changes in BEAS-2B cells were assessed following the exposure to cigarette smoke extract (CSE) and PM2.5.ResultsHigh levels of ambient PM2.5 were more strongly associated with high Saint George’s respiratory questionnaire specific for COPD (SGRQ-C) scores in currently smoking patients with COPD. Combined exposure to cigarette smoke and PM2.5 increased mean linear intercept and TUNEL-positive cells in lung tissue, which was associated with increased inflammatory cell infiltration and inflammatory cytokine release in mice. Exposure to a combination of CSE and PM2.5 reduced cell viability and upregulated NLRP3, caspase-1, IL-1β, and IL-18 transcription in BEAS-2B cells. NLRP3 silencing with siRNA reduced pyroptosis and restored cell viability.ConclusionsPM2.5 aggravates smoking-induced airway inflammation and cell death via pyroptosis. Clinically, PM2.5 deteriorates quality of life and may worsen prognosis in currently smoking patients with COPD.Graphical

Microscopic computed tomography with AI-CNN-powered image analysis: the path to phenotype bleomycin-induced lung injury.

Bleomycin (BLM)-induced lung injury in mice is a valuable model for investigating the molecular mechanisms that drive inflammation and fibrosis and for evaluating potential therapeutic approaches to treat the disease. Given high variability in the BLM model, it is critical to accurately phenotype the animals in the course of an experiment. In the present study, we aimed to demonstrate the utility of microscopic computed tomography (µCT) imaging combined with an artificial intelligence (AI)-convolutional neural network (CNN)-powered lung segmentation for rapid phenotyping of BLM mice. µCT was performed in freely breathing C57BL/6J mice under isoflurane anesthesia on days 7 and 21 after BLM administration. Terminal invasive lung function measurement and histological assessment of the left lung collagen content were conducted as well. µCT image analysis demonstrated gradual and time-dependent development of lung injury as evident by alterations in the lung density, air-to-tissue volume ratio, and lung aeration in mice treated with BLM. The right and left lung were unequally affected. µCT-derived parameters such as lung density, air-to-tissue volume ratio, and nonaerated lung volume correlated well with the invasive lung function measurement and left lung collagen content. Our study demonstrates the utility of AI-CNN-powered µCT image analysis for rapid and accurate phenotyping of BLM mice in the course of disease development and progression.NEW & NOTEWORTHY Microscopic computed tomography (µCT) imaging combined with an artificial intelligence (AI)-convolutional neural network (CNN)-powered lung segmentation is a rapid and powerful tool for noninvasive phenotyping of bleomycin mice over the course of the disease. This, in turn, allows earlier and more reliable identification of therapeutic effects of new drug candidates, ultimately leading to the reduction of unnecessary procedures in animals in pharmacological research.

Corilagin Inhibits Neutrophil Extracellular Trap Formation and Protects against Hydrochloric Acid/Lipopolysaccharide-Induced Acute Lung Injury in Mice by Suppressing the STAT3 and NOX2 Signaling Pathways.

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are characterized by uncontrolled inflammatory responses, neutrophil activation and infiltration, damage to the alveolar capillary membrane, and diffuse alveolar injury. Neutrophil extracellular traps (NETs), formed by activated neutrophils, contribute significantly to various inflammatory disorders and can lead to tissue damage and organ dysfunction. Corilagin, a compound found in Phyllanthus urinaria, possesses antioxidative and anti-inflammatory properties. In this study, we investigated the protective effects and underlying mechanisms of corilagin in hydrochloric acid (HCl)/lipopolysaccharide (LPS)-induced lung injury. Mice received intraperitoneal administration of corilagin (2.5, 5, or 10 mg/kg) or an equal volume of saline 30 min after intratracheal HCl/LPS administration. After 20 h, lung tissues were collected for analysis. Corilagin treatment significantly mitigated lung injury, as evidenced by reduced inflammatory cell infiltration, decreased production of proinflammatory cytokines, and alleviated oxidative stress. Furthermore, corilagin treatment suppressed neutrophil elastase expression, reduced NET formation, and inhibited the expression of ERK, p38, AKT, STAT3, and NOX2. Our findings suggest that corilagin inhibits NET formation and protects against HCl/LPS-induced ALI in mice by modulating the STAT3 and NOX2 signaling pathways.

LncRNA XIST modulates miR-328-3p ectopic expression in lung injury induced by tobacco-specific lung carcinogen NNK both in vitro and in vivo.

It is well acknowledged that tobacco-derived lung carcinogens can induce lung injury and even lung cancer through a complex mechanism. MicroRNAs (MiRNAs) are differentially expressed in tobacco-derived carcinogen nicotine-derived nitrosamine ketone (NNK)-treated A/J mice. RNA sequencing was used to detect the level of long non-coding RNAs (lncRNAs). Murine and human lung normal and cancer cells were used to evaluate the function of lncRNA XIST and miR-328-3p in vitro, and NNK-treated A/J mice were used to test their function in vivo. In vivo levels of miR-328-3p and lncRNA XIST were analysed, using in situ hybridization. miR-328-3p agomir and lncRNA XIST-specific siRNA were used to manipulate in vivo levels of miR-328-3p and lncRNA XIST in A/J mice. LncRNA XIST was up-regulated in NNK-induced lung injury and dominated the NNK-induced ectopic miRNA expression in NNK-induced lung injury both in vitro and in vivo. Either lncRNA XIST silencing or miR-328-3p overexpression exerted opposing effects in lung normal and cancer cells regarding cell migration. LncRNA XIST down-regulated miR-328-3p levels as a miRNA sponge, and miR-328-3p targeted the 3'-UTR of FZD7 mRNA, which is ectopically overexpressed in lung cancer patients. Both in vivo lncRNA XIST silencing and miR-328 overexpression could rescue NNK-induced lung injury and aberrant overexpression of the lung cancer biomarker CK19 in NNK-treated A/J mice. Our results highlight the promotive effect of lncRNA XIST in NNK-induced lung injury and elucidate its post-transcriptional mechanisms, indicating that targeting lncRNA XIST/miR-328-3p could be a potential therapeutic strategy to prevent tobacco carcinogen-induced lung injury in vivo.

Effect of ω-9MUFAs in Fat Emulsion on Serum Interleukin-6 in Rats with Lipopolysaccharide-induced Lung Injury.

This study aimed to investigate how ω-9 MUFAs in fat emulsion affect serum IL- 6 levels in rats with lipopolysaccharide (LPS)-induced lung injury. Research suggests that acute lung injury (ALI) develops acute respiratory distress syndrome (ARDS) due to the activation of many inflammatory factors. ALI may be treated by reducing inflammation. Fat emulsion is used in parenteral nutrition for critically ill patients to regulate the body's inflammatory response. It is mostly made up of ω-9 MUFAs (Clinoleic), which can regulate the inflammatory response. The effect of ω-9MUFAs on the secretion of IL-6 in ALI rats was studied in order to provide a basis for the rational use of fat emulsion in clinical practice and provide new ideas for the diagnosis and treatment of ALI. The control, model, and -9MUFAs groups consisted of 18 female Sprageue-Dawley (SD) young rats (180 ± 20 g). The SD young rats received normal saline and were not operated. LPS-induced ALI animals received tail vein injections of normal saline. SD young rats were first triggered with acute lung injury by LPS (3 mg/kg) and then injected with 3 mg/kg of ω-9MUFAs via the tail vein. The expression levels of IL-6, an activator of signal transduction transcription 3 (STAT3), transforming growth factor-β (TGF-β), and glycoprotein 130 (GP130) in serum and lung tissues were determined by ELISA and Western blot methods. Compared with the model group, the survival rate of rats in the ω-9 MUFAs group was significantly increased, and the difference was statistically significant (p<0.05). Compared with the model group, the lung pathology of rats in the ω-9 MUFAs group was significantly improved, and the expression levels of IL-6, TGF-β1, GP130, IL-1 and other proteins were significantly decreased. The difference was statistically significant (p<0.05). In LPS-induced lung injury, ω-9MUFAs may alleviate symptoms by inhibiting the IL-6/GP130/STAT3 pathway.

Application of dose-gradient function in reducing radiation induced lung injury in breast cancer radiotherapy.

Try to create a dose gradient function (DGF) and test its effectiveness in reducing radiation induced lung injury in breast cancer radiotherapy. Radiotherapy plans of 30 patients after breast-conserving surgery were included in the study. The dose gradient function was defined as DGH=VDVp3, then the area under the DGF curve of each plan was calculated in rectangular coordinate system, and the minimum area was used as the trigger factor, and other plans were triggered to optimize for area reduction. The dosimetric parameters of target area and organs at risk in 30 cases before and after re-optimization were compared. On the premise of ensuring that the target dose met the clinical requirements, the trigger factor obtained based on DGF could further reduce the V5, V10, V20, V30 and mean lung dose (MLD) of the ipsilateral lung in breast cancer radiotherapy, P < 0.01. And the D2cc and mean heart dose (MHD) of the heart were also reduced, P < 0.01. Besides, the NTCPs of the ipsilateral lung and the heart were also reduced, P < 0.01. The trigger factor obtained based on DGF is efficient in reducing radiation induced lung injury in breast cancer radiotherapy.

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.

Down-regulating lncRNA KCNQ1OT1 relieves type II alveolar epithelial cell apoptosis during one-lung ventilation via modulating miR-129-5p/HMGB1 axis induced pulmonary endothelial glycocalyx.

Endothelial glycocalyx (EG) maintains vascular homeostasis and is destroyed after one-lung ventilation (OLV)-induced lung injury. Long noncoding RNAs (lncRNAs) are critically involved in various lung injuries. This study aimed to investigate the role and regulatory mechanism of KCNQ1 overlapping transcript 1 (KCNQ1OT1) in OLV-induced lung injury and LPS-induced type II alveolar epithelial cell (AECII) apoptosis. The rat OLV model was established, and the effects of KCNQ1OT1 on OLV-induced ALI in vivo were explored. Bax and Caspase-3 expression in rat lung tissues was measured by immunochemistry (IHC). AECIIs were isolated from rat lungs and treated with LPS or normal saline (control) for in vitro analysis. The expression of KCNQ1OT1, miR-129-5p, and HMGB1 was measured by quantitative real-time PCR (qRT-PCR) or Western blot (WB). Cell proliferation and apoptosis were examined by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) and flow cytometry. The downstream targets of KCNQ1OT1 were predicted by bioinformatics, and the binding relationship between KCNQ1OT1 and miR-129-3p was verified by dual-luciferase reporter assays. The potential target of miR-129-5p was further explored on the Targetscan website and revealed to target HMGB1. Enzyme-linked immunosorbent assay (ELISA) or WB was adopted to determine the levels of IL-1β, TNF-α, MDA, SOD, heparanase (HPA), matrix metalloproteinase 9 (MMP9), heparan sulfate (HS) and syndecan-1 (SDC-1). KCNQ1OT1 and HMGB1 were up-regulated during OLV-induced lung injury, and their expression was positively correlated. KCNQ1OT1 knockdown reduced OLV-induced pulmonary edema and lung epithelial cell apoptosis, increased vascular permeability, reduced IL-1β, TNF-α, MDA, and SOD levels and glycocalyx markers by targeting miR-129-5p or upregulating HMGB1. Overexpressing KCNQ1OT1 promoted cell apoptosis, reduced cell proliferation, aggravated inflammation and oxidative stress, and up-regulated HMGB1, HPA and MMP9 in LPS-treated AECIIs, while the HMGB1 silencing showed the opposite effects. MiR-129-5p mimics partially eliminated the KCNQ1OT1-induced effects, while recombinant HMGB1 restored the effects of miR-129-5p overexpression on AECIIs. Additionally, KCNQ1OT1 was demonstrated to promote the activation of the p38 MAPK/Akt/ERK signaling pathways in AECIIs via HMGB1. KCNQ1OT1 knockdown alleviated AECII apoptosis and EG damage during OLV by targeting miR-129-5p/HMGB1 to inactivate the p38 MAPK/Akt/ERK signaling. The findings of our study might deepen our understanding of the molecular basis in OLV-induced lung injury and provide clues for the targeted disease management.

Functional roles of CD26/DPP4 in lipopolysaccharide-induced lung injury.

Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation and increased permeability of lung microvascular cells. CD26/dipeptidyl peptidase-4 (DPP4) is a type II membrane protein that is expressed in several cell types and mediates multiple pleiotropic effects. We previously reported that DPP4 inhibition by sitagliptin attenuates lipopolysaccharide (LPS)-induced lung injury in mice. The current study characterized the functional role of CD26/DPP4 expression in LPS-induced lung injury in mice, isolated alveolar macrophages, and cultured lung endothelial cells. In LPS-induced lung injury, inflammatory responses [bronchoalveolar lavage fluid (BALF) neutrophil numbers and several proinflammatory cytokine levels] were attenuated in Dpp4 knockout (Dpp4 KO) mice. However, multiple assays of alveolar capillary permeability were similar between the Dpp4 KO and wild-type mice. TNF-α and IL-6 production was suppressed in alveolar macrophages isolated from Dpp4 KO mice. In contrast, in cultured mouse lung microvascular endothelial cells (MLMVECs), reduction in CD26/DPP4 expression by siRNA resulted in greater ICAM-1 and IL-6 expression after LPS stimulation. Moreover, the LPS-induced vascular monolayer permeability in vitro was higher in MLMVECs treated with Dpp4 siRNA, suggesting that CD26/DPP4 plays a protective role in endothelial barrier function. In summary, this study demonstrated that genetic deficiency of Dpp4 attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential functional roles of CD26/DPP4 expression in resident cellular components of the lung. CD26/DPP4 may be a potential therapeutic target for ARDS and warrants further exploration to precisely identify the multiple functional effects of CD26/DPP4 in ARDS pathophysiology.NEW & NOTEWORTHY We aimed to clarify the functional roles of CD26/DPP4 in ARDS pathophysiology using Dpp4-deficient mice and siRNA reduction techniques in cultured lung cells. Our results suggest that CD26/DPP4 expression plays a proinflammatory role in alveolar macrophages while also playing a protective role in the endothelial barrier. Dpp4 genetic deficiency attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential roles of CD26/DPP4 expression in the resident cellular components of the lung.

The protective and antiapoptotic effects of Hypericum triquetrifolium Turra against cyclophosphamide-induced lung injury in rats: in vitro evaluation

Objectives: Hypericum triquetrifolium Turra (HTT) has been traditionally used in medical treatments due to its sedative, antiseptic, antiinflammatory, and anthelmintic properties. The present study aims to investigate the lung-protective and antiapoptotic effects of HTT against cyclophosphamide (CP)-induced lung injury in rats. Methods: Thirty-five Sprague Dawley rats were categorized into 5 groups, each consisting of seven members. Phenolic acid and flavonoid contents of this plant were determined. The lung tissue samples cultivated from the rats were examined in histopathological and immunohistochemically for the apoptosis markers of Caspase-3, Bax, and Bcl-2. Results: Histopathological results indicated that structural defects, bleeding areas, and edema had occurred in the lungs of the CP-Alone Group. Besides, Caspase-3 and Bax positivity of the lung cells had also increased while Bcl-2 positivity had decreased. On the other hand, in the HTT+CP Group, HTT was shown to have reversed the aforementioned changes positively. Conclusion: Based on in vivo results, HTT could be a strong protective candidate for CP-induced lung injury and apoptosis

Ficolin-A/2 Aggravates Severe Lung Injury through Neutrophil Extracellular Traps Mediated by Gasdermin D–Induced Pyroptosis

Neutrophil extracellular traps (NETs) and pyroptosis are critical events in lung injury. We aimed to investigate whether Ficolin-A influences NET formation through pyroptosis to exacerbate lipopolysaccharides (LPS)-induced lung injury. The expression of Ficolin-A/2, NETs, and pyroptosis-related molecules was investigated in animal and cell models. Knockout and knockdown (recombinant protein) methods were employed to elucidate regulatory mechanisms. Pearson's correlation coefficient was utilized to analyze the correlation between Ficolins and pyroptosis- and NET-related markers in clinical samples. In this study, Ficolin-2 (similar to Ficolin-A) showed significant overexpression in patients with acute respiratory distress syndrome (ARDS). In vivo, knockout of Ficolin-A, but not Ficolin-B, attenuated lung inflammation and inhibited NET formation in LPS-induced mouse model. DNaseI further alleviated lung inflammation and NET formation in Ficolin-A knockout mice. In vitro, neutrophils derived from Fcna-/- mice exhibited less pyroptosis and necroptosis than those from the control group after LPS stimulation. Additionally, gasdermin D (GSDMD) knockdown or Nod-like receptor protein 3 (NLRP3) inhibitor reduced NET formation. Addition of recombinant Ficolin-2 protein to human peripheral blood neutrophils promoted NET formation and pyroptosis after LPS stimulation, whereas Ficolin-2 knockdown had opposite effects. ARDS patients exhibited increased levels of pyroptosis- and NET-related markers, which were positively correlated with Ficolin-2 levels. In conclusion, these results suggested that Ficolin-A/2 exacerbated NET formation and LPS-induced lung injury via the GSDMD-mediated pyroptosis.

Betulinic acid attenuates T-2 toxin-induced lung injury by activating Nrf2 signaling pathway and inhibiting MAPK/NF-κB signaling pathway

T-2 toxin, a type-A trichothecene mycotoxin, exists ubiquitously in mildewed foods and feeds. Betulinic acid (BA), a pentacyclic triterpenoid derived from plants, has the effect of relieving inflammation and oxidative stress. The purpose of this study was to investigate whether BA mitigates lung impairment caused by T-2 toxin and elucidate the underlying mechanism. The results indicated that T-2 toxin triggered the inflammatory cell infiltration, morphological alterations and cell apoptosis in the lungs. It is gratifying that BA ameliorated T-2 toxin-caused lung injury. The protein expression of nuclear factor erythrocyte 2-related factor 2 (Nrf2) pathway and the markers of antioxidative capability were improved in T-2 toxin induced lung injury by BA mediated protection. Simultaneously, BA supplementation could suppress T-2 toxin-induced mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB)-dependent inflammatory response and mitochondrial apoptotic pathway. Therefore, T-2 toxin gave rise to pulmonary toxicity, but these changes were moderated by BA administration through regulation of the Nrf2/MAPK/NF-κB pathway, which maybe offer a viable alternative for mitigating the lung impairments caused by the mycotoxin.

Azacitidine induced lung injury: report and contemporary discussion on diagnosis and management.

Azacitidine, a hypomethylating agent, has caused a paradigm shift in the outcomes of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who are not eligible for stem cell transplantation, particularly in combination with BCL2 and IDH inhibitors. Azacitidine and Azacitidine-based combinations have been widely considered a safe low-intensity therapy when compared to traditional conventional treatments. The development of lung toxicity from azacitidine is not a well-characterized adverse event. However, if it happens, it can be fatal, especially if not recognized and treated promptly. In this review, we aim to familiarize the reader with the presentation of azacitidine-induced lung injury, provide our suggested approach to management based on our experience and the current understanding of its mechanism, and review the literature of 20 case reports available on this topic.

Multifaceted role of SARS-CoV-2 structural proteins in lung injury.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus to cause acute respiratory distress syndrome (ARDS) and contains four structural proteins: spike, envelope, membrane, and nucleocapsid. An increasing number of studies have demonstrated that all four structural proteins of SARS-CoV-2 are capable of causing lung injury, even without the presence of intact virus. Therefore, the topic of SARS-CoV-2 structural protein-evoked lung injury warrants more attention. In the current article, we first synopsize the structural features of SARS-CoV-2 structural proteins. Second, we discuss the mechanisms for structural protein-induced inflammatory responses in vitro. Finally, we list the findings that indicate structural proteins themselves are toxic and sufficient to induce lung injury in vivo. Recognizing mechanisms of lung injury triggered by SARS-CoV-2 structural proteins may facilitate the development of targeted modalities in treating COVID-19.

Meta analysis of the second course of radiotherapy for recurrent esophageal cancer1.

How to improve efficacy and reduce side effects in treating recurrent esophageal cancer by applying the second course of radiotherapy alone and its combination with chemotherapy has been attracting broad research interest. This review paper aims to systematically evaluate efficacy and side effects of applying the second course of anterograde radiotherapy alone and its combination with chemotherapy in treating recurrent esophageal cancer. First, the relevant research papers are retrieved from PubMed, CNKI and Wanfang databases. Next, Redman 5.3 software is used to calculate the relative risk and 95% confidence interval to evaluate the efficacy and adverse reactions of applying the single-stage radiotherapy with and without combining single/multi dose chemotherapy to treat recurrent esophageal cancer. Then, a meta data analysis is applied to examine the effectiveness and side effects of radiation alone and re-course radiotherapy plus chemotherapy in treating esophageal cancer recurrence after the first radiotherapy. Fifteen papers are retrieved, which included 956 patients. Among them, 476 patients received radiotherapy combined with single drug/multi drug chemotherapy (observation) and others received only radiotherapy (control). Data analysis results show that the incidence of radiation induced lung injury and bone marrow suppression is high in the observation group. Subgroup analysis also shows the higher effective rate or one-year overall survival rate of patients treated with the second course radiotherapy combined with single drug chemotherapy. The meta-analysis result demonstrates that combining the second course of radiotherapy with single-drug chemotherapy has advantages in treating recurrent esophageal cancer with the manageable side effects. However, due to insufficient data, it is not possible to conduct the further subgroup analysis comparing the side effects of restorative radiation with the combined chemotherapy using between a single drug and multiple drugs.

MgO Nanoparticle Synthesis, Chemical Delivery in Rat Model Induced Lung Injury

Acute lung injury is a disorder of acute inflammation that causes disruption of the lung endothelial and epithelial barriers. Acute Respiratory Distress Syndrome or ARDS is a diffuse inflammatory lung process that frequently manifests in critically ill patients, with an estimated incidence of 3 million people a year. Clinically, ARDS is manifested by bilateral or diffuse radiographic infiltrates, hypoxemia, decreased lung compliance, and increased ventilatory dead space. The histological manifestation of ARDS is diffuse alveolar damage as defined by epithelial injury, hyaline membrane formation and alveolar flooding with proteinaceous fluid, increase alveolar surface area and frequently neutrophilic inflammation. The animal model correlate to ARDS as an acute lung injury (ALI). Models were employed to test potential new therapeutic interventions and to investigate under-lying mechanistic pathways that lead to diffuse lung injury. In this study cage cigarette smoke model was used for an acute lung injury. For that purpose, thirty (30) young albino healthy rats were used, and their duration of trial was 21 days. Each group was given an oral drug administration containing MgO-150mg/kg, MgO-300mg/kg BW for treatment and diet schedule in young albino rats of male sex for the experimental procedure of 0 to 21 days. Mean body weight, BALF, lipid profile, liver profile and lung histology were assessed. Results revealed that MgO nanoparticles exhibited antioxidant capacity at dosages of 300mg/kg, and 150mg/kg. This formulation of selected nanoparticles at high dose exhibited an acute lung injury and antioxidant effects as compared to low dose extract. Additionally, transcriptional factors revealed up-regulation at high dose in contrast to the low dose extract in lung injury treated groups.

Estimation of normal lung weight index in healthy female domestic pigs

IntroductionLung weight is an important study endpoint to assess lung edema in porcine experiments on acute respiratory distress syndrome and ventilatory induced lung injury. Evidence on the relationship between lung–body weight relationship is lacking in the literature. The aim of this work is to provide a reference equation between normal lung and body weight in female domestic piglets.Materials and methods177 healthy female domestic piglets from previous studies were included in the analysis. Lung weight was assessed either via a CT-scan before any experimental injury or with a scale after autopsy. The animals were randomly divided in a training (n = 141) and a validation population (n = 36). The relation between body weight and lung weight index (lung weight/body weight, g/kg) was described by an exponential function on the training population. The equation was tested on the validation population. A Bland–Altman analysis was performed to compare the lung weight index in the validation population and its theoretical value calculated with the reference equation.ResultsA good fit was found between the validation population and the exponential equation extracted from the training population (RMSE = 0.060). The equation to determine lung weight index from body weight was: LungWeightIndexgkg=26.26∗10-0.011∗BodyWeightkg.\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{Lung}} {\ ext{Weight}} {\ ext{Index}} \\left(\\frac{{\ ext{g}}}{{\ ext{kg}}}\\right)=26.26*{10}^{-0.011*{\ ext{Body}} {\ ext{Weight}} \\left({\ ext{kg}}\\right)}.$$\\end{document} At the Bland and Altman analyses, the mean bias between the real and the expected lung weight index was − 0.26 g/kg (95% CI − 0.96–0.43), upper LOA 3.80 g/kg [95% CI 2.59–5.01], lower LOA − 4.33 g/kg [95% CI = − 5.54–(− 3.12)].ConclusionsThis exponential function might be a valuable tool to assess lung edema in experiments involving 16–50 kg female domestic piglets. The error that can be made due to the 95% confidence intervals of the formula is smaller than the one made considering the lung to body weight as a linear relationship.

Developing a Computational Model of Lungs for Patients With Acute Respiratory Distress Syndrome

Abstract Acute respiratory distress syndrome (ARDS) is a condition secondary to direct or indirect insult to lungs, leading to acute respiratory failure, and is associated with high mortality. Majority of the ARDS patients require mechanical ventilation, which acts as double-edged sword. Ventilator induced lung injury (VILI) is considered secondary to high inspiratory pressure and cyclical opening during inspiration, and collapse during expiration as suggested by ARDS network clinical trials. Other mechanism for VILI exist secondary to heterogeneous ventilation. To enumerate these mechanisms leading to VILI, a computational fluids dynamics (CFD) study was performed in this study to explore the flow patterns and the pressure distribution in a human tracheobronchial airway model from third to sixth generation branches. The authors validated the computational methodology and analyzed the results to obtain velocity profiles in the primary and secondary flow directions. The study investigated the role of various flow velocities corresponding to Reynolds number (Re) from 100 to 2000 on the pressure drops along branches and bifurcation zones. The identification of secondary flow patterns was critical in understanding the development of asymmetric velocity profiles in the triple bifurcation geometry. The observed patterns in pressure drops and velocity profiles over the laminar flow regime pave the path toward further development of a numerical model to aid treatment for patients with ARDS.

SARS-CoV-2 Accessory Protein Orf7b Induces Lung Injury via c-Myc Mediated Apoptosis and Ferroptosis.

The pandemic of coronavirus disease 2019 (COVID-19) has been the foremost modern global public health challenge. The airway is the primary target in severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection, with substantial cell death and lung injury being signature hallmarks of exposure. The viral factors that contribute to cell death and lung injury remain incompletely understood. Thus, this study investigated the role of open reading frame 7b (Orf7b), an accessory protein of the virus, in causing lung injury. In screening viral proteins, we identified Orf7b as one of the major viral factors that mediates lung epithelial cell death. Overexpression of Orf7b leads to apoptosis and ferroptosis in lung epithelial cells, and inhibitors of apoptosis and ferroptosis ablate Orf7b-induced cell death. Orf7b upregulates the transcription regulator, c-Myc, which is integral in the activation of lung cell death pathways. Depletion of c-Myc alleviates both apoptotic and ferroptotic cell deaths and lung injury in mouse models. Our study suggests a major role of Orf7b in the cell death and lung injury attributable to COVID-19 exposure, supporting it as a potential therapeutic target.

The Na/K-ATPase role as a signal transducer in lung inflammation.

Acute respiratory distress syndrome (ARDS) is marked by damage to the capillary endothelium and alveolar epithelium following edema formation and cell infiltration. Currently, there are no effective treatments for severe ARDS. Pathologies such as sepsis, pneumonia, fat embolism, and severe trauma may cause ARDS with respiratory failure. The primary mechanism of edema clearance is the epithelial cells' Na/K-ATPase (NKA) activity. NKA is an enzyme that maintains the electrochemical gradient and cell homeostasis by transporting Na+ and K+ ions across the cell membrane. Direct injury on alveolar cells or changes in ion transport caused by infections decreases the NKA activity, loosening tight junctions in epithelial cells and causing edema formation. In addition, NKA acts as a receptor triggering signal transduction in response to the binding of cardiac glycosides. The ouabain (a cardiac glycoside) and oleic acid induce lung injury by targeting NKA. Besides enzymatic inhibition, the NKA triggers intracellular signal transduction, fostering proinflammatory cytokines production and contributing to lung injury. Herein, we reviewed and discussed the crucial role of NKA in edema clearance, lung injury, and intracellular signaling pathway activation leading to lung inflammation, thus putting the NKA as a protagonist in lung injury pathology.