Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

Potential of exogenous melatonin administration to mitigate heat stress induce pathophysiology of chicken.

Melatonin (MT) is an amine hormone secreted by the body that has antioxidant and anti-inflammatory properties. The aim of this study was to investigate pathophysiological protection of MT in heat-stressed chickens. By modelling heat-stressed chickens and treating them with MT. After 21 days of administration, serum antioxidant enzymes, biochemical indices, inflammatory cytokine and heat-stress indices were detected, along with cardiopulmonary function indices and histological observations in chickens. The results show heat-stress induced a decrease (P < 0.05) in body weight and an increase in body temperature, which was reversed after MT intervention. Treatment with MT inhibited (P < 0.05) the secretion of pro-inflammatory factors interleukin-1ß, interleukin-6, tumor necrosis factor α, serum heat shock protein 70, corticosterone, and elevated (P < 0.05) the levels of biochemical factors total protein, albumin, globulin, and increased (P < 0.05) the activities of antioxidant enzymes superoxide dismutase, glutathione peroxidase and catalase in chicken serum caused by heat stress, and the best effect was observed with the medium dose of MT. The heat-stress caused cardiac atrophy and pulmonary congestion, decreased (P < 0.05) the cardiac function indices creatine kinase isoenzyme, cardiac troponin I, angiotensin receptor I, creatine kinase and lung function indices myeloperoxidase, angiotensin-II, heat shock factor I, and increased (P < 0.05) the lung vascular endothelial growth factor II. Sections of the heart and lungs after administration of MT were observed to be more complete with more normal tissue indices. At the same time, compared with heat stress, heart and lung function indices of grade chickens after MT administration were significantly (P < 0.05)reduced and tended to normal levels, and the best effect was observed in the medium-dose MT. In conclusion, heat stress can cause pathophysiological damage in chickens, and 1 mg/kg/d of exogenous melatonin can attenuate this adverse effect.

Lethality of SARS-CoV-2 infection-a comparative autopsy study focusing on COVID-19 development and virus variants.

AIMS: Different SARS-CoV-2 variants are driving various waves of infection of the corona pandemic. Official statistics provide no information on who died due to coronavirus disease 2019 (COVID-19) or an alternative disease during which SARS-CoV-2 infection was detected. The current study aims at addressing the effect of the different variants evolving during the pandemic on fatal outcomes. METHODS AND RESULTS: Standardised autopsies were performed on 117 people who died of a SARS-CoV-2 infection and the findings were interpreted in clinical and pathophysiological contexts. The typical histological sequence of COVID-19-related lung injury was detected independently of the disease-causing virus variant, but was significantly less common (50 versus 80-100%) and less severe in cases infected by omicron variants compared to precedent variants (P < 0.05). COVID-19 was less often the leading cause of death following omicron infection. Extrapulmonary manifestations of COVID-19 did not contribute to death in this cohort. Lethal COVID-19 may occur after complete SARS-CoV-2 vaccination. Reinfection was not the cause of death in any of the autopsies of this cohort. CONCLUSION: Autopsies represent the gold standard in determining the cause of death after SARS-CoV-2 infection and autopsy registers are currently the only available data source allowing for evaluation of which patients died of COVID-19 or with SARS-CoV-2 infection. Compared to previous variants, infection with an omicron variant affected the lungs less frequently and resulted in less severe lung disease.

N-acetyl cysteine mitigates lung damage and inflammation after chlorine exposure in vivo and ex vivo.

The objective of this study was to explore the effects of antioxidant treatments, specifically N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA), in a mouse model of chlorine (Cl2)-induced lung injury. Additionally, the study aimed to investigate the utility of pig precision-cut lung slices (PCLS) as an ex vivo alternative for studying the short-term effects of Cl2 exposure and evaluating antioxidant treatments. The toxicological responses were analyzed in Cl2-exposed mice (inflammation, airway hyperresponsiveness (AHR)) and PCLS (viability, cytotoxicity, inflammatory mediators). Airways contractions were assessed using a small ventilator for mice and electric-field stimulation (EFS) for PCLS. Antioxidant treatments were administered to evaluate their effects. In Cl2-exposed mice, NAC treatment did not alleviate AHR, but it did reduce the number of neutrophils in bronchoalveolar lavage fluid and inflammatory mediators in lung tissue. In PCLS, exposure to Cl2 resulted in concentration-dependent toxicity, impairing the lung tissue's ability to respond to EFS-stimulation. NAC treatment increased viability, mitigated the toxic responses caused by Cl2 exposure, and maintained contractility comparable to unexposed controls. Interestingly, NACA did not provide any additional treatment effect beyond NAC in both models. In conclusion, the establishment of a pig model for Cl2-induced lung damage supports further investigation of NAC as a potential treatment. However, the lack of protective effects on AHR after NAC treatment in mice suggests that NAC alone may not be sufficient as a complete treatment for Cl2 injuries. Optimization of existing medications with a polypharmacy approach may be more successful in addressing the complex sequelae of Cl2-induced lung injury.

Do alternative tobacco products induce less adverse respiratory risk than cigarettes?

RATIONALE: Due to the relatively short existence of alternative tobacco products, gaps exist in our current understanding of their long-term respiratory health effects. We therefore undertook the first-ever side-by-side comparison of the impact of chronic inhalation of aerosols emitted from electronic cigarettes (EC) and heated tobacco products (HTP), and combustible cigarettes (CC) smoke. OBJECTIVES: To evaluate the potential differential effects of alternative tobacco products on lung inflammatory responses and efficacy of vaccination in comparison to CC. METHODS: Mice were exposed to emissions from EC, HTP, CC, or air for 8 weeks. BAL and lung tissue were analyzed for markers of inflammation, lung damage, and oxidative stress. Another group was exposed for 12 weeks and vaccinated and challenged with a bacterial respiratory infection. Antibody titers in BAL and sera and pulmonary bacterial clearance were assessed. MAIN RESULTS: EC- and HTP-aerosols significantly augmented lung immune cell infiltrates equivalent to that achieved following CC-exposure. HTP and CC significantly increased neutrophil numbers compared to EC. All products augmented numbers of B cells, T cells, and pro-inflammatory IL17A+ T cells in the lungs. Decreased lung antioxidant activity and lung epithelial and endothelial damage was induced by all products. EC and HTP differentially augmented inflammatory cytokines/chemokines in the BAL. Generation of immunity following vaccination was impaired by EC and HTP but to a lesser extent than CC, with a CC > HTP > EC hierarchy of suppression of pulmonary bacterial clearance. CONCLUSIONS: HTP and EC-aerosols induced a proinflammatory pulmonary microenvironment, lung damage, and suppressed efficacy of vaccination.

Research progress on the effects of gut microbiome on lung damage induced by particulate matter exposure.

Air pollution is one of the top five causes of death in the world and has become a research hotspot. In the past, the health effects of particulate matter (PM), the main component of air pollutants, were mainly focused on the respiratory and cardiovascular systems. However, in recent years, the intestinal damage caused by PM and its relationship with gut microbiome (GM) homeostasis, thereby affecting the composition and function of GM and bringing disease burden to the host lung through different mechanisms, have attracted more and more attention. Therefore, this paper reviews the latest research progress in the effect of PM on GM-induced lung damage and its possible interaction pathways and explores the potential immune inflammatory mechanism with the gut-lung axis as the hub in order to understand the current research situation and existing problems, and to provide new ideas for further research on the relationship between PM pollution, GM, and lung damage.

Impairment of apoptosis pathway via Apaf1 downregulation during chlorpyrifos and/or cypermethrin induced lung damage.

Chlorpyrifos is an organophosphate and the cypermethrin is type 2 pyrethroid insecticide that are used for indoor and outdoor pest control. The present study aimed to investigate differential transcriptional profiling to identify the candidate gene associated with lung injury following exposure to chlorpyrifos and/or cypermethrin in a mouse model system. Swiss male albino mice (n = 24) were divided into three treatment groups (n = 6 each) that were given chlorpyrifos (2.76 mg kg-1 body weight), cypermethrin (2 mg kg-1 body weight) and the combination of both pesticides orally dissolved in corn oil and one control group (n = 6) that received corn oil for 90 days. The pulmonary expression of the Apaf1 was observed using RT2 Profiler PCR Array. The results showed that chronic exposure to chlorpyrifos, cypermethrin and their combination downregulated (67, 63 and 66 genes) and upregulated (4, 2 and 2 genes), respectively. The pulmonary expression of Apaf1 that plays important role in apoptosis was found to be downregulated. The immunohistochemistry depicted reduced expression of Apaf1 in both airway epithelium and alveolar septa following exposure to chlorpyrifos and/or cypermethrin. In conclusion, results demonstrated that exposure to chlorpyrifos, cypermethrin and their combination cause lung damage by the dysregulation of Apaf1 gene expression.

Evaluation of the Sensitivity of Prominent Biomarkers Involvement in Diagnosing the Severity of Lung Damage in Patients with COVID-19.

Background: COVID-19 has become the greatest pandemic of the century. Considering the role of some hematologic and biochemical factors and their alterations due to the activity of the immune system, the current study aimed to evaluate LDH/CRP/ESR/RDW in patients with COVID-19 and their relationship with the severity of lung involvement based on CT scan findings. Methods: In this cross-sectional study, some biomarkers (LDH/CRP/ESR/RDW) were measured in 158 patients who were admitted to the intensive care unit (ICU) or hospitalized in the infectious diseases ward of Rasoul-e-Akram and Firoozgar hospitals or attended to the outpatient clinics. The diagnosis was confirmed by a positive RT-PCR test in all patients. The severity of lung involvement was determined by CT scan findings for comparison. Data were collected and analyzed through SPSS version 22. Results: Regarding the severity of lung damage according to the CT scan, 17.7% of the patients were normal, 19% had less than 25% involvement, 17% had 25% -50% involvement, 33.5% had 50% -75% involvement, and 12% had more than 75% involvement. Considering the increasing severity of lung damage based on CT scans, the levels of RDW, ESR, CRP, and LDH significantly increased in parallel. The diagnostic value of RDW (cut-off point: 12.6, Sen: 73.1% (95%CI: 65.1-79.5), Sp: 53.6% (95%CI: 45.7-61.7), ESR (cut-off point: 49, Sen: 46.9% (95%CI: 38.2-54.5)), Sp: 85.7% (95%CI: 789.-90.5)), CRP (cut-off point: 23, Sen: 62.8% (95%CI: 54.6-70.4), Sp: 77.7% (95%CI: 70.3-84.1)) and LDH (cut-off point: 550, Sen: 65.1% (95%CI: 57.2-72.5), Sp: 85.7% (95%CI: 78.9-90.5)) were significant in diagnosing the severity of lung involvement (P < 0.05). Conclusion: The use of RDW, ESR, CRP, and LDH biomarkers could be effective in predicting the severity of lung damage in patients with COVID-19.

Neutrophils Contribute to Severity of Tuberculosis Pathology and Recovery From Lung Damage Pre- and Posttreatment.

BACKGROUND: Despite microbiological cure, about 50% of tuberculosis (TB) patients have poor lung recovery. Neutrophils are associated with lung pathology; however, CD16/CD62L-defined subsets have not been studied in TB. Using flow cytometry, we monitored frequencies, phenotype, and function of neutrophils following stimulation with Mycobacterium tuberculosis (Mtb) whole cell lysate (WCL) and ESAT-6/CFP-10 fusion protein (EC) in relation to lung pathology. METHODS: Fresh blood from 42 adult, human immunodeficiency virus (HIV)-negative TB patients were analyzed pre- and post-therapy, with disease severity determined using chest radiography and bacterial load. Flow cytometry was used to monitor frequencies, phenotype, and function (generation of reactive oxygen species [ROS], together with CD11b, tumor necrosis factor, and interleukin 10 [IL-10] expression) of neutrophils following 2-hour stimulation with Mtb-specific antigens. RESULTS: Total neutrophils decreased by post-treatment compared to baseline (P = .0059); however, CD16brCD62Lbr (segmented) neutrophils increased (P = .0031) and CD16dimCD62Lbr (banded) neutrophils decreased (P = .038). Banded neutrophils were lower in patients with severe lung damage at baseline (P = .035). Following WCL stimulation, ROS from segmented neutrophils was higher in patients with low Mtb loads even after adjusting for sex (P = .038), whereas IL-10-expressing CD16dimCD62Llo cells were higher in patients with mild damage (P = .0397) at baseline. CONCLUSIONS: High ROS generation, low levels of banded neutrophils, and high levels of IL-10-expressing CD16dimCD62Llo neutrophils are associated with reduced lung pathology at diagnosis. Hence, neutrophils are potential early indicators of TB severity and promising targets for TB host-directed therapy.

Recent evidence for toxic effects of NH3 exposure on lung injury: Protective effects of L-selenomethionine.

Ammonia (NH3) is a common air pollutant, which poses a serious threat to farm animals. L-selenomethionine is organic selenium (Se), which can inhibit intracellular ROS generation, block ROS-dependent autophagy, promote mitochondrial energy metabolism, and enhance the body's immunity. Lung, as an important organ of the respiratory system, is highly susceptible to the toxic effects of NH3. However, there were few studies on the mechanism of toxic effects of NH3 on lung tissues. The aim of this study was to investigate the effect of NH3 on the lungs in pigs and the alleviating effect of L-selenomethionine. Twenty-four Large White*Duroc*Min pigs were randomly assigned to 4 groups: control group, NH3 group, Se group, and NH3 +Se group. The results showed that exposure to NH3 caused damage and inflammation in lung tissues and significantly increased blood NH3 concentration. NH3 induced changes of oxidative stress indexes (GSH, GSH-Px, SOD, MDA, Keap1, Nrf2, and HO-1) and expressions of energy metabolism related genes (HK1, HK2, PFK, PK, LDHA, and HIF-1α). Ultrastructure showed that mitochondrial damage and autophagosome increased significantly, and the expression levels of autophagy related genes (Beclin1, ATG5, ATG7, ATG10, and p62) changed. However, the addition of L-selenomethionine alleviated the above changes, but there was still a significant difference compared with the control group (P < 0.05). This finding can provide a new evidence for mitigation of NH3 toxicity.

Genetic Deletion of Mmp9 Does Not Reduce Airway Inflammation and Structural Lung Damage in Mice with Cystic Fibrosis-like Lung Disease.

Elevated levels of matrix metalloprotease 9 (MMP-9) and neutrophil elastase (NE) are associated with bronchiectasis and lung function decline in patients with cystic fibrosis (CF). MMP-9 is a potent extracellular matrix-degrading enzyme which is activated by NE and has been implicated in structural lung damage in CF. However, the role of MMP-9 in the in vivo pathogenesis of CF lung disease is not well understood. Therefore, we used ß-epithelial Na+ channel-overexpressing transgenic (ßENaC-Tg) mice as a model of CF-like lung disease and determined the effect of genetic deletion of Mmp9 (Mmp9-/-) on key aspects of the pulmonary phenotype. We found that MMP-9 levels were elevated in the lungs of ßENaC-Tg mice compared with wild-type littermates. Deletion of Mmp9 had no effect on spontaneous mortality, inflammatory markers in bronchoalveolar lavage, goblet cell metaplasia, mucus hypersecretion and emphysema-like structural lung damage, while it partially reduced mucus obstruction in ßENaC-Tg mice. Further, lack of Mmp9 had no effect on increased inspiratory capacity and increased lung compliance in ßENaC-Tg mice, whereas both lung function parameters were improved with genetic deletion of NE. We conclude that MMP-9 does not play a major role in the in vivo pathogenesis of CF-like lung disease in mice.

Role of Mesenchymal Stem Cells and Extracellular Vesicles in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial fibrotic disease that leads to disability and death within 5 years of diagnosis. Pulmonary fibrosis is a disease with a multifactorial etiology. The concept of aberrant regeneration of the pulmonary epithelium reveals the pathogenesis of IPF, according to which repeated damage and death of alveolar epithelial cells is the main mechanism leading to the development of progressive IPF. Cell death provokes the migration, proliferation and activation of fibroblasts, which overproduce extracellular matrix, resulting in fibrotic deformity of the lung tissue. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising therapies for pulmonary fibrosis. MSCs, and EVs derived from MSCs, modulate the activity of immune cells, inhibit the expression of profibrotic genes, reduce collagen deposition and promote the repair of damaged lung tissue. This review considers the molecular mechanisms of the development of IPF and the multifaceted role of MSCs in the therapy of IPF. Currently, EVs-MSCs are regarded as a promising cell-free therapy tool, so in this review we discuss the results available to date of the use of EVs-MSCs for lung tissue repair.

Canavalia gladiata Pod Extract Mitigates Ovalbumin-Induced Asthma Onset in Male BALB/c Mice via Suppression of MAPK.

Asthma is one of the most common inflammatory diseases of the lung worldwide. There has been considerable progress in recent studies to treat and prevent allergic asthma, however, various side effects are still observed in clinical practice. Six-week-old male BALB/c mice were orally administered with either sword bean pod extracts (SBP; 100 or 300 mg/kg) or dexamethasone (DEX; 5 mg/kg) once daily over 3 weeks, followed by ovalbumin sensitization (OVA/Alum.; intraperitoneal administration, 50 µg/2 mg/per mouse). Scoring of lung inflammation was performed to observe pathological changes in response to SBP treatment compared to OVA/Alum.-induced lung injury. Additionally, inflammatory cytokines were quantified in serum, bronchoalveolar lavage fluid (BALF), and lung tissue using ELISA and Western blot analyses. SBP treatment significantly reduced the infiltration of inflammatory cells, and release of histamine, immunoglobulin E, and leukotriene in serum and BALF. Moreover, the therapeutic effect of SBP was also assessed to analyze the inflammatory changes in the lung tissues. SBP markedly suppressed the activation of the MAPK signaling pathway and the expression of key inflammatory proteins (e.g., TNF-α) and Th2 type cytokines (IL-5 and IL-13). SBP was effective in ameliorating the allergic inflammation against OVA/Alum.-induced asthma by suppressing pulmonary inflammation.

An Entropy-Based Measure of Complexity: An Application in Lung-Damage.

The computed tomography (CT) chest is a tool for diagnostic tests and the early evaluation of lung infections, pulmonary interstitial damage, and complications caused by common pneumonia and COVID-19. Additionally, computer-aided diagnostic systems and methods based on entropy, fractality, and deep learning have been implemented to analyse lung CT images. This article aims to introduce an Entropy-based Measure of Complexity (EMC). In addition, derived from EMC, a Lung Damage Measure (LDM) is introduced to show a medical application. CT scans of 486 healthy subjects, 263 diagnosed with COVID-19, and 329 with pneumonia were analysed using the LDM. The statistical analysis shows a significant difference in LDM between healthy subjects and those suffering from COVID-19 and common pneumonia. The LDM of common pneumonia was the highest, followed by COVID-19 and healthy subjects. Furthermore, LDM increased as much as clinical classification and CO-RADS scores. Thus, LDM is a measure that could be used to determine or confirm the scored severity. On the other hand, the d-summable information model best fits the information obtained by the covering of the CT; thus, it can be the cornerstone for formulating a fractional LDM.

Germinal Center-Induced Immunity Is Correlated With Protection Against SARS-CoV-2 Reinfection But Not Lung Damage.

Germinal centers (GCs) elicit protective humoral immunity through a combination of antibody-secreting cells and memory B cells, following pathogen invasion or vaccination. However, the possibility of a GC response inducing protective immunity against reinfection following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown. We found GC activity was consistent with seroconversion observed in recovered macaques and humans. Rechallenge with a different clade of virus resulted in significant reduction in replicating virus titers in respiratory tracts in macaques with high GC activity. However, diffuse alveolar damage and increased fibrotic tissue were observed in lungs of reinfected macaques. Our study highlights the importance of GCs developed during natural SARS-CoV-2 infection in managing viral loads in subsequent infections. However, their ability to alleviate lung damage remains to be determined. These results may improve understanding of SARS-CoV-2-induced immune responses, resulting in better coronavirus disease 2019 (COVID-19) diagnosis, treatment, and vaccine development.

Harmful Effects of Granulocytic Myeloid-Derived Suppressor Cells on Tuberculosis Caused by Hypervirulent Mycobacteria.

BACKGROUND: The role of myeloid-derived suppressor cells (MDSCs) in patients with severe tuberculosis who suffer from uncontrolled pulmonary inflammation caused by hypervirulent mycobacterial infection remains unclear. METHODS: This issue was addressed using C57BL/6 mice infected with highly virulent Mycobacterium bovis strain MP287/03. RESULTS: CD11b+GR1int population increased in the bone marrow, blood and lungs during advanced disease. Pulmonary CD11b+GR1int (Ly6GintLy6Cint) cells showed granularity similar to neutrophils and expressed immature myeloid cell markers. These immature neutrophils harbored intracellular bacilli and were preferentially located in the alveoli. T-cell suppression occurred concomitantly with CD11b+GR1int cell accumulation in the lungs. Furthermore, lung and bone marrow GR1+ cells suppressed both T-cell proliferation and interferon γ production in vitro. Anti-GR1 therapy given when MDSCs infiltrated the lungs prevented expansion and fusion of primary pulmonary lesions and the development of intragranulomatous caseous necrosis, along with increased mouse survival and partial recovery of T-cell function. Lung bacterial load was reduced by anti-GR1 treatment, but mycobacteria released from the depleted cells proliferated extracellularly in the alveoli, forming cords and clumps. CONCLUSIONS: Granulocytic MDSCs massively infiltrate the lungs during infection with hypervirulent mycobacteria, promoting bacterial growth and the development of inflammatory and necrotic lesions, and are promising targets for host-directed therapies.

IL-36 Cytokines Promote Inflammation in the Lungs of Long-Term Smokers.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with high morbidity and mortality. The IL-36 family are proinflammatory cytokines that are known to shape innate immune responses, including those critical to bacterial pneumonia. The objective of this study was to determine whether IL-36 cytokines promote a proinflammatory milieu in the lungs of long-term smokers with and without COPD. Concentrations of IL-36 cytokines were measured in plasma and BAL fluid from subjects in a pilot study (n = 23) of long-term smokers with and without COPD in vivo and from a variety of lung cells (from 3-5 donors) stimulated with bacteria or cigarette smoke components in vitro. Pulmonary macrophages were stimulated with IL-36 cytokines in vitro, and chemokine and cytokine production was assessed. IL-36α and IL-36γ are produced to varying degrees in murine and human lung cells in response to bacterial stimuli and cigarette smoke components in vitro. Moreover, whereas IL-36γ production is upregulated early after cigarette smoke stimulation and wanes over time, IL-36α production requires a longer duration of exposure. IL-36α and IL-36γ are enhanced systemically and locally in long-term smokers with and without COPD, and local IL-36α concentrations display a positive correlation with declining ventilatory lung function and increasing proinflammatory cytokine concentrations. In vitro, IL-36α and IL-36γ induce proinflammatory chemokines and cytokines in a concentration-dependent fashion that requires IL-36R and MyD88. IL-36 cytokine production is altered in long-term smokers with and without COPD and contributes to shaping a proinflammatory milieu in the lungs.

Blockade of PD-1 decreases neutrophilic inflammation and lung damage in experimental COPD.

Chronic obstructive lung disease (COPD) and lung cancer are both caused by smoking and often occur as comorbidity. The programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis is an important canonic immunoregulatory pathway, and antibodies that specifically block PD-1 or PD-L1 have demonstrated efficacy as therapeutic agents for non-small cell lung cancer. The role of the PD-1/PD-L1 axis in the pathogenesis of COPD is unknown. Here, we analyzed the function of the PD-1/PD-L1 axis in preclinical COPD models and evaluated the concentrations of PD-1 and PD-L1 in human serum and bronchoalveolar lavage (BAL) fluids as biomarkers for COPD. Anti-PD-1 treatment decreased lung damage and neutrophilic inflammation in mice chronically exposed to cigarette smoke (CS) or nontypeable Haemophilus influenzae (NTHi). Ex vivo stimulated macrophages obtained from anti-PD-1-treated mice released reduced amounts of inflammatory cytokines. PD-L1 concentrations correlated positively with PD-1 concentrations in human serum and BAL fluids. Lung sections obtained from patients with COPD stained positive for PD-L1. Our data indicate that the PD-1/PD-L1 axis is involved in developing inflammation and tissue destruction in COPD. Inflammation-induced activation of the PD-1 pathway may contribute to disease progression.

Tobacco smoking confers risk for severe COVID-19 unexplainable by pulmonary imaging.

BACKGROUND: COVID-19 is a new pneumonia. It has been hypothesized that tobacco smoking history may increase severity of this disease in the patients once infected by the underlying coronavirus SARS-CoV-2 because smoking and COVID-19 both cause lung damage. However, this hypothesis has not been tested. OBJECTIVE: Current study was designed to focus on smoking history in patients with COVID-19 and test this hypothesis that tobacco smoking history increases risk for severe COVID-19 by damaging the lungs. METHODS AND RESULTS: This was a single-site, retrospective case series study of clinical associations, between epidemiological findings and clinical manifestations, radiographical or laboratory results. In our well-characterized cohort of 954 patients including 56 with tobacco smoking history, smoking history increased the risk for severe COVID-19 with an odds ratio (OR) of 5.5 (95% CI: 3.1-9.9; P = 7.3 × 10-8 ). Meta-analysis of ten cohorts for 2891 patients together obtained an OR of 2.5 (95% CI: 1.9-3.3; P < 0.00001). Semi-quantitative analysis of lung images for each of five lobes revealed a significant difference in neither lung damage at first examination nor dynamics of the lung damage at different time-points of examinations between the smoking and nonsmoking groups. No significant differences were found either in laboratory results including D-dimer and C-reactive protein levels except different covariances for density of the immune cells lymphocyte (P = 3.8 × 10-64 ) and neutrophil (P = 3.9 × 10-46 ). CONCLUSION: Tobacco smoking history increases the risk for great severity of COVID-19 but this risk is achieved unlikely by affecting the lungs.

The effects of edaravone, a free-radical scavenger in lung injury induced by valproic acid demonstrated via different biochemical parameters.

In this study, we aimed to evaluate whether edaravone (EDA) has a protective role against valproic acid (VPA)-induced lung damage via its antioxidative activity. Male Sprague-Dawley rats were split into four groups. Control (n = 8) rats; rats given EDA (30 mg kg-1 day-1 ; n = 10); rats given only (VPA, 500 mg kg-1 day-1 ; n = 10); rats given VPA + EDA (in the same dose and time) for 7 days. EDA and VPA were applied intraperitoneally. After 8 days, lung tissues were immediately taken from the rats. In lung homogenates, reduced glutathione, total antioxidant status levels, and superoxide dismutase, glutathione peroxidase, sodium/potassium ATPase, paraoxonase1, and carbonic anhydrase activities significantly abated, whereas catalase, glutathione reductase, glutathione-S-transferase activities insignificantly decreased in the VPA-treated group. In contrast, lipid peroxidation, reactive oxygen species, and total oxidant status levels, glycoprotein and protein carbonyl contents, nitric oxide, hydroxyproline levels, and xanthine oxidase, lactate dehydrogenase, arginase, and prolidase activities significantly increased in the VPA-given group. Administration of EDA caused the reverse effects. As a consequence, EDA prevented oxidative stress-mediated lung injury via its robust antioxidant effects.