Lung Dysfunction Research Articles

Hyperoxia induces alveolar epithelial cell apoptosis by regulating mitochondrial function through small mothers against decapentaplegic 3 (SMAD3) and extracellular signal-regulated kinase 1/2 (ERK1/2)

ABSTRACT Oxygen therapy and mechanical ventilation are widely used to treat and manage neonatal emergencies in critically ill newborns. However, they are often associated with adverse effects and result in conditions such as chronic lung disease and bronchopulmonary dysplasia. Hence, aclear understanding of the mechanisms underlying hyperoxia-induced lung damage is crucial in order to mitigate the side effects of oxygen-based therapy. Here, we have established an in vitro model of hyperoxia-induced lung damage in type II alveolar epithelial cells (AECIIs) and delineated the molecular basis of oxygen therapy-induced impaired alveolar development. Thus, AECIIs were exposed to a hyperoxic environment and their cell viability, cell cycle progression, apoptosis, mitochondrial integrity and dynamics, and energy metabolism were assessed. The results showed that hyperoxia has no significant effect as an inhibitor of SMAD3 and ERK1/2 in AECIIs, but leads to significant inhibition of cell viability. Further, hyperoxia was found to promote AECII apoptosis and mitochondrial, whereas chemical inhibition of SMAD3 or ERK1/2 further exacerbated the detrimental effects of hyperoxia in AECIIs. Overall, these findings presented herein demonstrate the critical role of SMAD/ERK signaling in the regulation of AECII behavior in varying oxygen environments. Thus, this study offers novel insights for the prevention of neonatal lung dysfunction in premature infants.

Eculizumab in patients with severe coronavirus disease 2019 (COVID-19) requiring continuous positive airway pressure ventilator support: Retrospective cohort study

Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. In this single-centre, academic, unblinded study two 900 mg eculizumab doses were added-on standard therapy in ten COVID-19 patients admitted from February 2020 to April 2020 and receiving Continuous-Positive-Airway-Pressure (CPAP) ventilator support from ≤24 hours. We compared their outcomes with those of 65 contemporary similar controls. Primary outcome was respiratory rate at one week of ventilator support. Secondary outcomes included the combined endpoint of mortality and discharge with chronic complications. Baseline characteristics of eculizumab-treated patients and controls were similar. At baseline, sC5b-9 levels, ex vivo C5b-9 and thrombi deposition were increased. Ex vivo tests normalised in eculizumab-treated patients, but not in controls. In eculizumab-treated patients respiratory rate decreased from 26.8±7.3 breaths/min at baseline to 20.3±3.8 and 18.0±4.8 breaths/min at one and two weeks, respectively (p<0.05 for both), but did not change in controls. Between-group changes differed significantly at both time-points (p<0.01). Changes in respiratory rate correlated with concomitant changes in ex vivo C5b-9 deposits at one (rs = 0.706, p = 0.010) and two (rs = 0.751, p = 0.032) weeks. Over a median (IQR) period of 47.0 (14.0-121.0) days, four eculizumab-treated patients died or had chronic complications versus 52 controls [HRCrude (95% CI): 0.26 (0.09-0.72), p = 0.010]. Between-group difference was significant even after adjustment for age, sex and baseline serum creatinine [HRAdjusted (95% CI): 0.30 (0.10-0.84), p = 0.023]. Six patients and 13 controls were discharged without complications [HRCrude (95% CI): 2.88 (1.08-7.70), p = 0.035]. Eculizumab was tolerated well. The main study limitations were the relatively small sample size and the non-randomised design. In patients with severe COVID-19, eculizumab safely improved respiratory dysfunction and decreased the combined endpoint of mortality and discharge with chronic complications. Findings need confirmation in randomised controlled trials.

Pesticides Use and Impaired Lung Function Among Male Agricultural Farmers in Rural Sindh, Pakistan.

Use of pesticides implicated in decrement in lung function, manifested as restrictive or obstructive dysfunction or both. Using comparative cross-sectional study design, authors conducted the study to determine an association of pesticide use with impairment in lung function (restrictive/obstructive pattern of lung function) among agricultural farmers. The data were collected using modified American Thoracic Society Division of Lung Disease (ATS-DLD-78A) questionnaire and spirometer measurements. Using multinomial logistic regression, the risk of both restrictive and obstructive lung dysfunction was found to be almost twice among pesticides users with each increasing year of exposure to pesticides (1.92 and 1.95, respectively) after adjusting for other covariates. There is a need for reliable monitoring and reporting procedures along with appropriate environmental policies and regulations for handling of pesticides. Interventional studies are needed where farmers could be trained on the proper use of personal protective equipment (PPE) to limit the exposure to pesticides.

Diagnostic Overview of COVID-19 Patients with Comorbid Type 2 Diabetes Mellitus at Royal Prima General Hospital Medan in 2020

COVID-19 is a disease caused by infection with a coronavirus known as SARS-CoV-2. COVID-19 patients with diabetes have a poor prognosis and thus have a shorter life expectancy than those without diabetes. This is because COVID-19 causes severe lung dysfunction and inflammation. The purpose of the study is to find out the description of diagnostic of COVID-19 patients with comorbid diabetes mellitus type 2 at Royal Prima general hospital Medan in 2020. The case study design method is descriptive with a retrospective approach, the sample size of 63 patient medical records is taken by purposive sampling, a complete medical record and analyzed with descriptive statistics. Most patients were aged more than 50 years old (66.7%) and female (50.8%). With symptoms of fever (84.1%), cough (87.3%), shortness of breath (87.3%), headache (28.6%), diarrhea (9.5%), nausea (42.9%), abdominal pain (31.7%), loss of smell (20.6%). The longest hospitalization time (11-20 days) (46%). It can be concluded that the most age is &gt; 50 years, the most gender is female and the most clinical symptoms are cough and shortness of breath.

Reduced Lung Function and Progression to Prediabetes: A Prospective Study

Objective: Prediabetes is a state that people have blood glucose levels higher than normal but still not in diabetes range. There is a close relationship between impaired lung function and diabetes mellitus (DM). Reduced lung function can be present before the clinical evidence of diabetes or insulin resistance. Materials and Methods: The total number of subjects in this longitudinal study was 503 and compared with apparently healthy Kashmiri adults. All the subjects, at the time of their first visit, underwent Fasting Plasma Glucose (FPG) estimation, 2- hour oral glucose tolerance test (OGTT) and spirometry (FVC, FEV1 &amp; FEV1/FVC). Those subjects who had normal glucose tolerance (NGT) were retested for glycemic status and spirometric values after a follow-up period of 2-18 (mean=10) months. Results: Out of total 503 subjects on follow up 483 (96%) had NGT and 20 (4%) had prediabetes. Percent predicted forced vital capacity (FVC) and % predicted forced expiratory volume in 1st second (FEV1) were significantly lower (P-value&lt; 0.001) while as % predicted FEV1/FVC was significantly higher (P-value&lt; 0.001) in prediabetes as compared to NGT group. Conclusion: Results of our study point out a predominantly restrictive pattern of lung dysfunction in the prediabetes group as compared to the NGT group.

Individualized airway atomization improves preoperative lung dysfunction in patients with chronic rhinosinusitis with nasal polyps.

Individualized airway atomization improves preoperative lung dysfunction in patients with chronic rhinosinusitis with nasal polyps.

Fisetin suppresses cigarette smoke extract-induced epithelial to mesenchymal transition of airway epithelial cells through regulating COX-2/MMPs/β-catenin pathway

Cigarette smoke exposure leads to upregulation of cyclooxygenase‐2 (COX‐2), an inducible enzyme that synthesizes prostaglandin E2 (PGE2) and promotes airway inflammation. COX-2 overexpression is frequently implicated in inflammation, invasion, metastasis, and epithelial-mesenchymal transition (EMT). However, its detailed molecular mechanism in cigarette smoke induced EMT is not clear. Further, fisetin, a bioflavonoid, exhibits antioxidant and anti-inflammatory properties, but its effect in modulating COX-2-mediated inflammation and downstream sequelae remains unexplored. Therefore, we have investigated the mechanism of cigarette smoke-induced COX-2-mediated EMT in airway epithelial cells and examined the role of fisetin in controlling this aberration. MTT, trypan blue staining, gelatin zymography, Western blotting, invasion, wound healing, and tumor sphere formation assays in cigarette smoke extract (CSE) and/or fisetin treated airway epithelial cells, and in-silico molecular docking studies were performed. Results revealed that CSE exposure increased the expression and activity of COX-2, MMP-2/9, and β-catenin and also enhanced expression of EMT markers leading to higher migration and invasion potential of airway epithelial cells. A specific COX-2 inhibitor NS-398 as well as fisetin treatment reversed the expression of EMT biomarkers, reduced the activity of MMP-2/9, and blocked the migration and invasion potential induced by CSE. Further, PGE2 also increased MMPs activity, invasion, and migration potential similar to CSE, which were significantly reversed by fisetin. In-silico studies showed a high binding affinity of fisetin to key EMT associated proteins, validating its anti-EMT potential. Thus, our study firstly unearths the mechanism of CSE-induced EMT in airway epithelial cells via COX-2/MMP/β-catenin pathway, and secondly, it reveals that fisetin could significantly reverse CSE-induced EMT by inhibiting COX-2, indicating that fisetin could be an effective drug candidate for cigarette smoke-induced lung dysfunction.

25-Hydroxy vitamin D and body composition are associated with pulmonary function in non-cystic fibrosis bronchiectasis: A cross-sectional study

Previous studies have emphasized the effects of vitamin D on the lung function of cystic fibrosis (CF) adult patients. The main aim of the present study sought to determine the association between circulating 25-hydroxyvitamin D (25-OH D) concentration and clinical outcomes in non-cystic fibrosis (non-CF) bronchiectasis subjects. Secondary, we assessed the possible relationship between body composition and respiratory dysfunction in these patients. Sixty-two non-CF bronchiectasis patients (24 male/38 female), aged 18-72, were recruited in this cross-sectional study. Anthropometric indices, lung function tests, and bronchiectasis severity valuations were determined. Body composition, including Mid-arm muscle circumference (MAMC, cm) was calculated using triceps skinfold (TSF,mm) and mid-arm circumference (MAC,cm) under the reference formula. Then serum 25-hydroxyvitamin D concentration and C-reactive protein level were measured. The correlation between vitamin D level and pulmonary function and disease exacerbation tests was primarily assessed. Additionally, we evaluated the correlation between body composition and lung function tests. Circulating 25-hydroxyvitamin D status positively was correlated with lung function tests, including FEV1 (r=0.30, p value=0.035) and FVC (r=0.36, p value=0.011), and also be associated with the extent of pulmonary involvement (r=-0.34, p value=0.03). There was a significant negative correlation between percentage body fat and respiratory function, FEV1/FVC ratio (r=-0.43, p value<0.001). In contrast, there was a strong correlation between skeletal muscle mass and pulmonary function tests (r=0.26, p value=0.04). There is a positive association between low 25-hydroxyvitamin D status and lung dysfunction in participants with non-CF bronchiectasis. The pulmonary dysfunction also correlated with more percentage body fat and low skeletal muscle mass in these patients. Therefore, the evaluation of body composition and serum vitamin D are suggested in the disease management of the patients with non-CF bronchiectasis. However, these associations should be interpreted with caution due to the likelihood of reverse causation. More high-quality prospective studies are warranted to confirm our observations and determine the mechanisms underlying these findings.

Influence of surgical stabilization of clavicle fractures in multiply-injured patients with thoracic trauma

Thoracic trauma has decisive influence on the outcome of multiply-injured patients and is often associated with clavicle fractures. The affected patients are prone to lung dysfunction and multiple organ failure. A multi-center, retrospective analysis of patient records documented in the TraumaRegister DGU was performed to assess the influence of surgical stabilization of clavicle fractures in patients with thoracic trauma. A total of 3,209 patients were included in the analysis. In 1362 patients (42%) the clavicle fracture was treated operatively after 7.1 ± 5.3 days. Surgically treated patients had a significant reduction in lung failure (p = 0.013, OR = 0.74), multiple organ failure (p = 0.001, OR = 0.64), intubation time (p = 0.004; −1.81 days) and length of hospital stay (p = 0.014; −1.51 days) compared to non-operative treatment. Moreover, surgical fixation of the clavicle within five days following hospital admission significantly reduced the rates of lung failure (p = 0.01, OR = 0.62), multiple organ failure (p = 0.01, OR = 0.59) and length of hospital stay (p = 0.01; −2.1 days). Based on our results, multiply-injured patients with thoracic trauma and concomitant clavicle fracture may benefit significantly from surgical stabilization of a clavicle fracture, especially when surgery is performed within the first five days after hospital admission.

Isolation of Mitochondria From Fresh Mice Lung Tissue.

Direct analysis of isolated mitochondria enables a better understanding of lung dysfunction. Despite well-defined mitochondrial isolation protocols applicable to other tissues, such as the brain, kidney, heart, and liver, a robust and reproductive protocol has not yet been advanced for the lung. We describe a protocol for the isolation of mitochondria from lung tissue aiming for functional analyses of mitochondrial O2 consumption, transmembrane potential, reactive oxygen species (ROS) formation, ATP production, and swelling. We compared our protocol to that used for heart mitochondrial function that is well-established in the literature, and achieved similar results.

Benzo(a)pyrene induces airway epithelial injury through Wnt5a-mediated non-canonical Wnt-YAP/TAZ signaling

Wnt5a is a key mediator of non-canonical Wnt signaling, and an early indicator of epithelial injury and lung dysfunction. Polycyclic aromatic hydrocarbons (PAHs) could induce acute pulmonary pathogenesis, of which the underlying mechanism remains unclear. To elucidate the potential role of Wnt5a-mediated non-canonical Wnt-YAP/TAZ signaling in the lung injury induced by short-term exposure of benzo(a)pyrene (BaP, a representative PAHs), intratracheally instilled mouse model was used and further interfered with its Wnt5a level by small molecule antagonists and agonists. Our data revealed that BaP exposure induced the lung inflammatory response and reduced the expression of Clara cell secretory protein (CC16) in a dose-dependent manner. More importantly, the activation of Wnt5a and downstream YAP/TAZ were accompanied with the enhanced release of epithelial-derived thymic stromal lymphopoietin and interleukin-33, which acted as pro-inflammatory cytokines. Functionally, inhibition of Wnt5a attenuated the BaP-induced inflammation and recuperated CC16 expression, as well as suppressed the epithelial cytokines release. Whereas promoting Wnt5a expression affected the toxic effects of BaP oppositely. Our findings together suggest that Wnt5a is a potential endogenous regulator in lung inflammation and airway epithelial injury, and Wnt5a-YAP/TAZ signaling contributes to lung dysfunction in acute exposure to BaP.

Genetic Correlation and Bidirectional Causal Association Between Type 2 Diabetes and Pulmonary Function.

BackgroundObservational studies have shown possible bidirectional association between type 2 diabetes (T2D) and pulmonary function, but the causality is not well defined. The purpose of this study is to investigate genetic correlation and causal relationship of T2D and glycemic traits with pulmonary function.MethodsBy leveraging summary statistics from large-scale genome-wide association studies, linkage disequilibrium score regression was first implemented to quantify genetic correlations between T2D, glycemic traits, and several spirometry indices. Then both univariable and multivariable Mendelian randomization analyses along with multiple pleiotropy-robust methods were performed in two directions to assess the causal nature of these relationships.ResultsForced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) showed significant genetic correlations with T2D and fasting insulin levels and suggestive genetic correlations with fasting glucose and hemoglobin A1c. In Mendelian randomization analyses, genetically predicted higher FEV1 (OR = 0.77; 95% CI = 0.63, 0.94) and FVC (OR = 0.82; 95% CI = 0.68, 0.99) were significantly associated with lower risk of T2D. Conversely, genetic predisposition to higher risk of T2D exhibited strong association with reduced FEV1 (beta = −0.062; 95% CI = −0.100, −0.024) and FEV1 (beta = −0.088; 95% CI = −0.126, −0.050) and increased FEV1/FVC ratio (beta = 0.045; 95% CI = 0.012, 0.078). We also found a suggestive causal effect of fasting glucose on pulmonary function and of pulmonary function on fasting insulin and proinsulin.ConclusionsThe present study provided supportive evidence for genetic correlation and bidirectional causal association between T2D and pulmonary function. Further studies are warranted to clarify possible mechanisms related to lung dysfunction and T2D, thus offering a new strategy for the management of the two comorbid diseases.

Eosinophils mediate SIgA production triggered by TLR2 and TLR4 to control Ascaris suum infection in mice.

Human ascariasis is the most prevalent but neglected tropical disease in the world, affecting approximately 450 million people. The initial phase of Ascaris infection is marked by larval migration from the host’s organs, causing mechanical injuries followed by an intense local inflammatory response, which is characterized mainly by neutrophil and eosinophil infiltration, especially in the lungs. During the pulmonary phase, the lesions induced by larval migration and excessive immune responses contribute to tissue remodeling marked by fibrosis and lung dysfunction. In this study, we investigated the relationship between SIgA levels and eosinophils. We found that TLR2 and TLR4 signaling induces eosinophils and promotes SIgA production during Ascaris suum infection. Therefore, control of parasite burden during the pulmonary phase of ascariasis involves eosinophil influx and subsequent promotion of SIgA levels. In addition, we also demonstrate that eosinophils also participate in the process of tissue remodeling after lung injury caused by larval migration, contributing to pulmonary fibrosis and dysfunction in re-infected mice. In conclusion, we postulate that eosinophils play a central role in mediating host innate and humoral immune responses by controlling parasite burden, tissue inflammation, and remodeling during Ascaris suum infection. Furthermore, we suggest that the use of probiotics can induce eosinophilia and SIgA production and contribute to controlling parasite burden and morbidity of helminthic diseases with pulmonary cycles.

Effect of patient–ventilator asynchrony on lung and diaphragmatic injury in experimental acute respiratory distress syndrome in a porcine model

BackgroundPatient–ventilator asynchrony during mechanical ventilation may exacerbate lung and diaphragm injury in spontaneously breathing subjects. We investigated whether subject–ventilator asynchrony increases lung or diaphragmatic injury in a porcine model of acute respiratory distress syndrome (ARDS). MethodsARDS was induced in adult female pigs by lung lavage and injurious ventilation before mechanical ventilation by pressure assist–control for 12 h. Mechanically ventilated pigs were randomised to breathe spontaneously with or without induced subject–ventilator asynchrony or neuromuscular block (n=7 per group). Subject–ventilator asynchrony was produced by ineffective, auto-, or double-triggering of spontaneous breaths. The primary outcome was mean alveolar septal thickness (where thickening of the alveolar wall indicates worse lung injury). Secondary outcomes included distribution of ventilation (electrical impedance tomography), lung morphometric analysis, inflammatory biomarkers (gene expression), lung wet-to-dry weight ratio, and diaphragmatic muscle fibre thickness. ResultsSubject-ventilator asynchrony (median [interquartile range] 28.8% [10.4] asynchronous breaths of total breaths; n=7) did not increase mean alveolar septal thickness compared with synchronous spontaneous breathing (asynchronous breaths 1.0% [1.6] of total breaths; n=7). There was no difference in mean alveolar septal thickness throughout upper and lower lung lobes between pigs randomised to subject–ventilator asynchrony vs synchronous spontaneous breathing (87.3–92.2 μm after subject–ventilator asynchrony, compared with 84.1–95.0 μm in synchronised spontaneous breathing;). There were also no differences between groups in wet-to-dry weight ratio, diaphragmatic muscle fibre thickness, atelectasis, lung aeration, or mRNA expression levels for inflammatory cytokines pivotal in ARDS pathogenesis. ConclusionsSubject–ventilator asynchrony during spontaneous breathing did not exacerbate lung injury and dysfunction in experimental porcine ARDS.

Ultramicronized Palmitoylethanolamide in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation.

Disseminated intravascular coagulation (DIC) is a severe condition characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. In the last years, it represents one of the most frequent consequences of coronavirus disease 2019 (COVID-19). The pathogenesis of DIC is complex, with cross-talk between the coagulant and inflammatory pathways. The objective of this study is to investigate the anti-inflammatory action of ultramicronized palmitoylethanolamide (um-PEA) in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by continual infusion of LPS (30 mg/kg) for 4 h through the tail vein. Um-PEA (30 mg/kg) was given orally 30 min before and 1 h after the start of intravenous infusion of LPS. Results showed that um-PEA reduced alteration of coagulation markers, as well as proinflammatory cytokine release in plasma and lung samples, induced by LPS infusion. Furthermore, um-PEA also has the effect of preventing the formation of fibrin deposition and lung damage. Moreover, um-PEA was able to reduce the number of mast cells (MCs) and the release of its serine proteases, which are also necessary for SARS-CoV-2 infection. These results suggest that um-PEA could be considered as a potential therapeutic approach in the management of DIC and in clinical implications associated to coagulopathy and lung dysfunction, such as COVID-19.

Biofilm Formation in Methicillin-Resistant Staphylococcus aureus Isolated in Cystic Fibrosis Patients Is Strain-Dependent and Differentially Influenced by Antibiotics.

Cystic fibrosis (CF) is a genetic disease with lung abnormalities making patients particularly predisposed to pulmonary infections. Staphylococcus aureus is the most frequently identified pathogen, and multidrug-resistant strains (MRSA, methicillin-resistant S. aureus) have been associated with more severe lung dysfunction leading to eradication recommendations. Diverse bacterial traits and adaptive skills, including biofilm formation, may, however, make antimicrobial therapy challenging. In this context, we compared the ability of a collection of genotyped MRSA isolates from CF patients to form biofilm with and without antibiotics (ceftaroline, ceftobiprole, linezolid, trimethoprim, and rifampicin). Our study used standardized approaches not previously applied to CF MRSA, the BioFilm Ring test® (BRT®), the Antibiofilmogram®, and the BioFlux™ 200 system which were adapted for use with the artificial sputum medium (ASM) mimicking conditions more relevant to the CF lung. We included 63 strains of 10 multilocus sequence types (STs) isolated from 35 CF patients, 16 of whom had chronic colonization. The BRT® showed that 27% of the strains isolated in 37% of the patients were strong biofilm producers. The Antibiofilmogram® performed on these strains showed that broad-spectrum cephalosporins had the lowest minimum biofilm inhibitory concentrations (bMIC) on a majority of strains. A focus on four chronically colonized patients with inclusion of successively isolated strains showed that ceftaroline, ceftobiprole, and/or linezolid bMICs may remain below the resistance thresholds over time. Studying the dynamics of biofilm formation by strains isolated 3years apart in one of these patients using BioFlux™ 200 showed that inhibition of biofilm formation was observed for up to 36h of exposure to bMIC and ceftaroline and ceftobiprole had a significantly greater effect than linezolid. This study has brought new insights into the behavior of CF MRSA which has been little studied for its ability to form biofilm. Biofilm formation is a common characteristic of prevalent MRSA clones in CF. Early biofilm formation was strain-dependent, even within a sample, and not only observed during chronic colonization. Ceftaroline and ceftobiprole showed a remarkable activity with a long-lasting inhibitory effect on biofilm formation and a conserved activity on certain strains adapted to the CF lung environment after years of colonization.

Dietary Phytoestrogens Ameliorate Hydrochloric Acid-Induced Chronic Lung Injury and Pulmonary Fibrosis in Mice.

We previously reported that female mice exhibit protection against chemically induced pulmonary fibrosis and suggested a potential role of estrogen. Phytoestrogens act, at least in part, via stimulation of estrogen receptors; furthermore, compared to residents of Western countries, residents of East Asian countries consume higher amounts of phytoestrogens and exhibit lower rates of pulmonary fibrosis. Therefore, we tested the hypothesis that dietary phytoestrogens ameliorate the severity of experimentally induced pulmonary fibrosis. Male mice placed on either regular soybean diet or phytoestrogen-free diet were instilled with 0.1 N HCl to provoke pulmonary fibrosis. Thirty days later, lung mechanics were measured as indices of lung function and bronchoalveolar lavage fluid (BALF) and lung tissue were analyzed for biomarkers of fibrosis. Mice on phytoestrogen-free diet demonstrated increased mortality and stronger signs of chronic lung injury and pulmonary fibrosis, as reflected in the expression of collagen, extracellular matrix deposition, histology, and lung mechanics, compared to mice on regular diet. We conclude that dietary phytoestrogens play an important role in the pathogenesis of pulmonary fibrosis and suggest that phytoestrogens (e.g., genistein) may be useful as part of a therapeutic regimen against hydrochloric acid-induced lung fibrosis and chronic lung dysfunction.

Transcriptomic Analysis of Polyhexamethyleneguanidine-Induced Lung Injury in Mice after a Long-Term Recovery.

Polyhexamethyleneguanidine phosphate (PHMG-P) is one of the causative agents of humidifier disinfectant-induced lung injury. Direct exposure of the lungs to PHMG-P causes interstitial pneumonia with fibrosis. Epidemiological studies showed that patients with humidifier disinfectant-associated lung injuries have suffered from restrictive lung function five years after the onset of the lung injuries. We investigated whether lung damage was sustained after repeated exposure to PHMG-P followed by a long-term recovery and evaluated the adverse effects of PHMG-P on mice lungs. Mice were intranasally instilled with 0.3 mg/kg PHMG-P six times at two weeks intervals, followed by a recovery period of 292 days. Histopathological examination of the lungs showed the infiltration of inflammatory cells, the accumulation of extracellular matrix in the lung parenchyma, proteinaceous substances in the alveoli and bronchiolar–alveolar hyperplasia. From RNA-seq, the gene expression levels associated with the inflammatory response, leukocyte chemotaxis and fibrosis were significantly upregulated, whereas genes associated with epithelial/endothelial cells development, angiogenesis and smooth muscle contraction were markedly decreased. These results imply that persistent inflammation and fibrotic changes caused by repeated exposure to PHMG-P led to the downregulation of muscle and vascular development and lung dysfunction. Most importantly, this pathological structural remodeling induced by PHMG-P was not reversed even after long-term recovery.

Interaction of Severe Acute Respiratory Syndrome Coronavirus 2 and Diabetes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a worldwide epidemic. It spreads very fast and hits people of all ages, especially patients with underlying diseases such as diabetes. In this review, we focus on the influences of diabetes on the outcome of SARS-CoV-2 infection and the involved mechanisms including lung dysfunction, immune disorder, abnormal expression of angiotensin-converting enzyme 2 (ACE2), overactivation of mechanistic target of rapamycin (mTOR) signaling pathway, and increased furin level. On the other hand, SARS-CoV-2 may trigger the development of diabetes. It causes the damage of pancreatic β cells, which is probably mediated by ACE2 protein in the islets. Furthermore, SARS-CoV-2 may aggravate insulin resistance through attacking other metabolic organs. Of note, certain anti-diabetic drugs (OADs), such as peroxisome proliferator-activated receptor γ (PPARγ) activator and glucagon-like peptide 1 receptor (GLP-1R) agonist, have been shown to upregulate ACE2 in animal models, which may increase the risk of SARS-CoV-2 infection. However, Metformin, as a first-line medicine for the treatment of type 2 diabetes mellitus (T2DM), may be a potential drug benefiting diabetic patients with SARS-CoV-2 infection, probably via a suppression of mTOR signaling together with its anti-inflammatory and anti-fibrosis function in lung. Remarkably, another kind of OADs, dipeptidyl Peptidase 4 (DPP4) inhibitor, may also exert beneficial effects in this respect, probably via a prevention of SARS-CoV-2 binding to cells. Thus, it is of significant to identify appropriate OADs for the treatment of diabetes in the context of SARS-CoV-2 infections.

Nontuberculous Mycobacterial Pulmonary Infection Among Lung Transplant Recipients.

Data are limited regarding the clinical significance of nontuberculous mycobacteria pulmonary infections among lung transplant recipients. We investigated the incidence and characteristics of pulmonary nontuberculous mycobacteria infection in ourlung transplant patient population. We obtaineddata of the patients who underwent lung transplant in our center from January 1997 to March 2019. Of 690 patients, nontuberculous mycobacteria were identified in 58 patients (8.4%) over a median follow-up of 3 years. Types of species were as follows: Mycobacterium simiae (n = 24), avium complex (n = 12), abscessus (n = 9), fortuitum (n = 6), chelonae (n = 2), szulgai (n = 1), kansasii (n = 1), lentiflavum (n = 1), and undefined mycobacteria (n = 2). When we compared infections in the early versus late period posttransplant (before and after 6 months), infections with Mycobacterium simiae (16 vs 8 incidents) and Mycobacterium fortuitum (5 vs 1 incident) were more often observed within the early period, whereas most Mycobacterium abscessus (7 vs 1 incident) and Mycobacterium avium complex (9 vs 3 incidents) were observed in the later period. The median forced expiratory volume in 1 second overtime did not differ significantly between patients with and without nontuberculous mycobacteria infection (P = .29). Nontuberculous mycobacteria acquisition was significantly associated with decreased survival (relative risk of 2.41, 95% CI, 1.70-3.43; P ⟨ .001). The nontuberculous mycobacteria species isolated varied according to the time elapsed since transplant. Among lung transplant recipients, nontuberculous mycobacteria infection was associated with increased mortality but not with lung dysfunction.