A deep insight into ferroptosis in lung disease: facts and perspectives.

In the last decade, ferroptosis has received much attention from the scientific research community. It differs from other modes of cell death at the morphological, biochemical, and genetic levels. Ferroptosis is mainly characterized by non-apoptotic iron-dependent cell death caused by iron-dependent lipid peroxide excess and is accompanied by abnormal iron metabolism and oxidative stress. In recent years, more and more studies have shown that ferroptosis is closely related to the occurrence and development of lung diseases. COPD, asthma, lung injury, lung fibrosis, lung cancer, lung infection and other respiratory diseases have become the third most common chronic diseases worldwide, bringing serious economic and psychological burden to people around the world. However, the exact mechanism by which ferroptosis is involved in the development and progression of lung diseases has not been fully revealed. In this manuscript, we describe the mechanism of ferroptosis, targeting of ferroptosis related signaling pathways and proteins, summarize the relationship between ferroptosis and respiratory diseases, and explore the intervention and targeted therapy of ferroptosis for respiratory diseases.

Prevalence and risk factors for postinfectious cough in discharged patients with coronavirus disease 2019 (COVID-19).

Background: Cough is one of the most common symptoms of coronavirus disease 2019 (COVID-19). However, the prevalence of persistent cough in recovered patients with COVID-19 during a longer follow-up remained unknown. This study aims to investigate the prevalence, and risk factors for postinfectious cough in COVID-19 patients after discharge. Methods: We conducted a follow-up study for 129 discharged patients with laboratory-confirmed COVID-19 in two large hospitals located in Hubei Province, China from January 2020 to December 2020. Baseline demographics, comorbidities and smoking history were extracted from the medical record. Current symptoms and severity were recorded by a uniform questionnaire. Spirometry, diffuse function and chest computed tomography (CT) were performed on part of patients who were able to return to the outpatient department at follow-up. Results: The median (interquartile range) follow-up time was 8.1 (7.9-8.5) months after discharge. The mean (standard deviation) age was 51.5 (14.9) years and 57 (44.2%) were male. A total of 27 (20.9%) patients had postinfectious cough (>3 weeks), 6 patients (4.7%) had persistent cough by the end of follow-up, including 3 patients with previous chronic respiratory diseases or current smoking. Other symptoms included dyspnea (6, 4.7%), sputum (4, 3.1%), fatigue (4, 3.1%), and anorexia (4, 3.1%) by the end of follow-up. Thirty-six of 41 (87.8%) patients showed impaired lung function or diffuse function, and 39 of 50 (78.0%) patients showed abnormal CT imaging. Patients with postinfectious cough demonstrated more severe and more frequent cough during hospitalization (P<0.001), and more chronic respiratory diseases (P=0.01). In multivariate logistic regression analysis, digestive symptoms during hospitalization [odds ratio (OR) 2.95, 95% confidence interval (CI): 1.10-7.92] and current smoking (OR 6.95, 95% CI: 1.46-33.14) were significantly associated with postinfectious cough of COVID-19. Conclusions: A small part of patients developed postinfectious cough after recovery from COVID-19, few patients developed chronic cough in spite of a higher proportion of impaired lung function and abnormal lung CT image. Current smoking and digestive symptoms during hospitalization were risk factors for postinfectious cough in COVID-19.

Efficacy and safety of Bufei Huoxue capsules in the management of convalescent patients with COVID-19 infection: A multicentre, double-blind, and randomised controlled trial.

BACKGROUND: As of September 17, 2021, coronavirus disease 2019 (COVID-19) has infected more than 226 million people in a worldwide pandemic, with conservative estimates suggesting that there are more than 204 million convalescent patients with COVID-19. Previous studies have indicated that patients in the recovery phase exhibit decreased function of multiple organs. In China, traditional Chinese medicine (TCM) treatment is recommended in the rehabilitation period of COVID-19; however, the safety and efficacy of such treatment remain to be confirmed. AIM OF STUDY: The present study aimed to evaluate the efficacy and safety of Bufei Huoxue (BFHX) in restoring the functional status and exercise tolerance of patients recovering from COVID-19. METHODS: A total of 131 patients in the rehabilitation period of COVID-19 infection were randomly divided into a Bufei Huoxue (BFHX) group (n = 66) and a placebo group (n = 65). BFHX or placebo was given orally three times a day (1.4 g/dose) for 90 days. The primary outcomes was to evaluate improvements in exercise tolerance and imaging manifestations on chest computed tomography (CT). RESULTS: After the exclusion of two patients who withdrew prior to receiving any medications, 129 patients were recruited, including 64 patients in the BFHX group and 65 patients in the placebo group. After 3 months of treatment, the BFHX group exhibited greater attenuation of pneumonia lesions on chest CT than the placebo group (P<0.05). Improvements in 6-min walk distance (6MWD) relative to baseline were also significantly better in the BFHX group than in the placebo group (P<0.01). Scores on the Fatigue Assessment Inventory (FAI) were lower in the BFHX group than in the placebo group (P<0.05). Although the rate of adverse events was higher in the BFHX group than in the placebo group (9.38% vs. 4.62%), the difference was not significant (P=0.3241). CONCLUSIONS: BFHX may exert strong rehabilitative effects on physiological activity in patients recovering from COVID-19, which may in turn attenuate symptoms of fatigue and improve exercise tolerance.

Virtual Reality Exposure Therapy (VRET) for Anxiety Due to Fear of COVID-19 Infection: A Case Series.

Virtual reality exposure therapy (VRET) is becoming popular for treating phobia and anxiety disorder. The recent pandemic of COVID-19 not only causes infection per se but also has an impact on mental health. This case series aimed to explore the role of VRET in the intervention of psychiatric illnesses with chief complaints of fear of COVID-19 infection. In vivo exposure therapy for fear of COVID-19 infection is not possible due to the risk of virus infection; in this scenario, the VRET provides an immersive experience and can act as adjunctive therapy for treating phobias and anxiety disorders arising due to novel coronavirus pandemic. Clinical presentation and findings as well as management and procedures of VRET are discussed. Medical record of three patients (two male and one female) at the Shenzhen Mental Health Center (Shenzhen Kangning Hospital), China, was included in the present case series. Patients were assessed with the Hamilton Anxiety Rating Scale and Fear of COVID-19 Scale to measure anxiety and fear, respectively. Throughout VRET sessions, we gradually and systematically exposed the patient to virtual COVID-19 scenarios (for example, touching stained door handle which may have viruses, watching pandemic news, watching frontline health care workers, etc.). In our study, VRET intervention significantly reduced the related symptoms caused by fear of COVID-19 infection. Furthermore, virtual reality can provide relevant theoretical and practical support for exploring the remote psychological counseling of patients in isolation wards.

Follistatin-like 1 protects mesenchymal stem cells from hypoxic damage and enhances their therapeutic efficacy in a mouse myocardial infarction model.

BACKGROUND: Cell therapy remains the most promising approach against ischemic heart injury. However, poor survival of engrafted cells in ischemic sites diminishes its therapeutic efficacy. Follistatin-like 1 (Fstl1) is documented as a novel pro-survival cardiokine for cardiomyocytes, and it is protective during ischemic heart injury. In the present study, we characterize the potential of Fstl1 as an effective strategy to enhance hypoxia resistance of donor cells and optimize stem cell-based therapy. METHODS: Murine bone marrow-derived mesenchymal stem cells (MSCs) were expanded in monolayer culture and characterized by flow cytometry. MSCs were subjected to hypoxia to mimic cardiac ischemic environment. Expression of Fstl1 was monitored 0, 24, and 48 h following hypoxia. Constitutive expression of Fstl1 in MSCs was achieved by lentivirus-mediated Fstl1 overexpression. Genetically modified MSCs were further collected for cell death and proliferation assay following 48 h of hypoxic treatment. Acute myocardial infarction (MI) model was created by ligating the left anterior descending coronary artery, while control MSCs (MSCs-mCherry) or Fstl1-overexpressing MSCs (MSCs-Fstl1) were injected into the peri-infarct zone simultaneously. Subsequently, retention of the donor cells was evaluated on post-therapy 1, 3, & 7 days. Finally, myocardial function, infarct size, inflammation, and neovascularization of the infarcted hearts were calculated thereafter. RESULTS: Expression of Fstl1 in hypoxic MSCs declines dramatically in a time-dependent manner. In vitro study further demonstrated that Fstl1 promotes survival and proliferation of hypoxic MSCs. Moreover, Fstl1 significantly prolongs MSC survival/retention after implantation. Finally, transplantation with Fstl1-overexpressing MSCs significantly improves post-MI cardiac function by limiting scar formation, reducing inflammatory response, and enhancing neovascularization. CONCLUSIONS: Our results suggest Fstl1 is an intrinsic cardiokine promoting survival and proliferation of MSCs, thereby optimizing their engraftment and therapeutic efficacy during cell therapy.

Two-stage study of lung cancer risk modification by a functional variant in the 3'-untranslated region of SMAD5 based on the bone morphogenetic protein pathway.

Increasing evidence supports a key role for the bone morphogenetic protein (BMP) signaling pathway in lung vasculogenesis and angiogenesis. Genetic variations in BMP genes have been found to be correlated with cancer risk. In particular, the mutation in the 3'-untranslated region of BMPs may significantly affect gene function, leading to cancer susceptibility. The aim of the present study was to determine whether genetic variations in the components of the BMP family are associated with lung cancer risk. A total of 314 tag single-nucleotide polymorphisms were identified in 18 genes, which are considered to either compose or regulate BMPs, and their association with lung cancer risk was evaluated in a two-stage case-control study with 4,680 cases and controls. A consistently significant association of SMAD5 rs12719482 with elevated lung cancer risk was observed in the three types of sources of populations (adjusted additive model in the combined population: Odds ratio=1.32, 95% confidence interval: 1.16-1.51). The lung cancer risk statistically significantly increased with the increasing number of variant alleles of SMAD5 rs12719482 in a dose-dependent pattern (P for trend=4.9×10-5). Consistent evidence was identified for a significant interaction between the rs12719482 and cigarette smoking, performed as either a continuous or discrete variable. These findings indicated that SMAD5 rs12719482 may be a possible candidate marker for susceptibility to lung cancer in the Chinese population.

Genetic Variants in the Hedgehog Interacting Protein Gene Are Associated with the FEV1/FVC Ratio in Southern Han Chinese Subjects with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Convincing evidences have demonstrated the associations between HHIP and FAM13a polymorphisms and COPD in non-Asian populations. Here genetic variants in HHIP and FAM13a were investigated in Southern Han Chinese COPD. METHODS: A case-control study was conducted, including 989 cases and 999 controls. The associations between SNPs genotypes and COPD were performed by a logistic regression model; for SNPs and COPD-related phenotypes such as lung function, COPD severity, pack-year of smoking, and smoking status, a linear regression model was employed. Effects of risk alleles, genotypes, and haplotypes of the 3 significant SNPs in the HHIP gene on FEV1/FVC were also assessed in a linear regression model in COPD. RESULTS: The mean FEV1/FVC% value was 46.8 in combined COPD population. None of the 8 selected SNPs apparently related to COPD susceptibility. However, three SNPs (rs12509311, rs13118928, and rs182859) in HHIP were associated significantly with the FEV1/FVC% (Pmax = 4.1 × 10-4) in COPD adjusting for gender, age, and smoking pack-years. Moreover, statistical significance between risk alleles and the FEV1/FVC% (P = 2.3 × 10-4), risk genotypes, and the FEV1/FVC% (P = 3.5 × 10-4) was also observed in COPD. CONCLUSIONS: Genetic variants in HHIP were related with FEV1/FVC in COPD. Significant relationships between risk alleles and risk genotypes and FEV1/FVC in COPD were also identified.

Identification of TRPCs genetic variants that modify risk for lung cancer based on the pathway and two-stage study.

OBJECTIVE: Store operated calcium channels (SOCCs) and Receptor-operated calcium channels (ROCCs) are important pathways participating in regulation of intracellular Ca(2 +) concentration in various cell types. The purpose of our study is to determine whether genetic variations in key components of SOCCs and ROCCs are associated with lung cancer risk. METHODS: We identified 236 tagSNPs in 9 key genes related to SOCCs and ROCCs (TRPC1, TRPC3, TRPC4, TRPC6, TRPC7, ORAI1, ORAI2, STIM1, and STIM2) and evaluated their association with lung cancer risk in a two-stage case-control study with a total of 2433 lung cancer cases and 2433 cancer-free controls using Illumina high throughput genotyping platform. RESULTS: We found consistently significant associations of TRPC4 rs9547991 and rs978156, and TRPC7 rs11748198 with increased risk of lung cancer among the three kinds of sources of populations (additive model in combined population: adjusted OR = 1.33, 95% CI = 1.11-1.59 for rs9547991; adjusted OR = 1.21, 95% CI = 1.08-1.35 for rs978156; and adjusted OR = 1.28, 95% CI = 1.10-1.47 for rs11748198). When combining the effects of TRPC7 rs11748198, and TRPC4 rs9547991 and rs978156, subjects carrying "≥ 1" variant alleles had a 1.29-fold increased risk of lung cancer (95% CI = 1.15-1.46), compared with those carrying "0" variant allele. Lung cancer risk significantly increased with the increasing number of variant alleles of the three SNPs in a dose-dependent manner (P for trend = 7.2 × 10(- 7)). CONCLUSION: These findings suggested that TRPC4 rs9547991 and rs978156, and TRPC7 rs11748198 were candidate susceptibility markers for lung cancer in Chinese population. Our study provides the epidemiological evidence supporting a connection between TRPC members and lung cancer risks.

Protein phosphatase 2A regulatory subunit B56ß modulates erythroid differentiation.

Anemia due to attenuated erythroid terminal differentiation is one of the most common hematological disorders occurring at all stages of life. We previously demonstrated that catalytic subunit α of protein phosphatase 2A (PP2Acα) modulates fetal liver erythropoiesis. However the corresponding PP2A regulatory subunit in this process remains unknown. In this study, we report that chemical inhibition of PP2A activity with okadaic acid impairs hemin-induced erythroid differentiation. Interestingly, B56 family member B56ß is the only regulatory subunit whose expression is induced by both erythropoietin in fetal liver cells and hemin in erythroleukemia K562 cells. Finally, knockdown of B56ß attenuates hemin-induced K562 erythroid differentiation. Collectively, our data identify B56ß as the potential functional regulatory subunit of PP2A in erythroid differentiation, shedding light on new target for precise modulation of PP2A activity for treatment of anemia and related diseases.

Immunomodulation by mesenchymal stem cells in treating human autoimmune disease-associated lung fibrosis.

BACKGROUND: Interstitial pneumonia in connective tissue diseases (CTD-IP) featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells (MSCs) may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts (HLFs) from patients pathologically diagnosed with usual interstitial pneumonia (UIP) and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals (HBMSCs) on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell (Treg) level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of α-smooth muscle actin (α-SMA). The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis (IPF). HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked α-SMA activation in CTD-UIP HLFs through a TGF-ß1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-ß1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice. CONCLUSIONS: Impairment of TGF-ß signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-ß1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.

Genetic variants in MUC4 gene are associated with lung cancer risk in a Chinese population.

Mucin MUC4, which is encoded by the MUC4 gene, plays an important role in epithelial cell proliferation and differentiation. Aberrant MUC4 overexpression is associated with invasive tumor proliferation and poor outcome in epithelial cancers. Collectively, the existing evidence suggests that MUC4 has tumor-promoter functions. In this study, we performed a case-control study of 1,048 incident lung cancer cases and 1,048 age- and sex frequency-matched cancer-free controls in a Chinese population to investigate the role of MUC4 gene polymorphism in lung cancer etiology. We identified nine SNPs that were significantly associated with increased lung cancer risk (P = 0.0425 for rs863582, 0.0333 for rs842226, 0.0294 for rs842225, 0.0010 for rs2550236, 0.0149 for rs2688515, 0.0191 for rs 2641773, 0.0058 for rs3096337, 0.0077 for rs859769, and 0.0059 for rs842461 in an additive model). Consistent with these single-locus analysis results, the haplotype analyses revealed an adverse effect of the haplotype "GGC" of rs3096337, rs859769, and rs842461 on lung cancer. Both the haplotype and diplotype "CTGAGC" of rs863582, rs842226, rs2550236, rs842225, and rs2688515 had an adverse effect on lung cancer, which is also consistent with the single-locus analysis. Moreover, we observed statistically significant interactions for rs863582 and rs842461 in heavy smokers. Our results suggest that MUC4 gene polymorphisms and their interaction with smoking may contribute to lung cancer etiology.

Successful thrombolysis in postoperative patients with acute massive pulmonary embolism.

PURPOSE: The standard medical management for patients with acute massive pulmonary embolism (MPE) is systemic thrombolysis. However, it is generally thought that recent surgeries are a contraindication to thrombolytic therapy. In this study, we evaluated the efficacy and safety of systemic thrombolysis for postoperative patients with acute MPE and assessed the risk of bleeding. METHODS: A retrospective review was performed on 21 postoperative patients with MPE in a timeframe of five years (from 2005 to 2010). The criteria for study inclusion were postoperative patients who received systemic thrombolysis for confirmed acute MPE within three weeks after surgery. RESULTS: Seventeen postoperative patients, including men (12) and women (five) aged 53±16 (range 23-71) years, were treated with systemic thrombolysis. Significant haemodynamic improvement (shock index<0.9) was observed in 16 of 17 cases (94%). The remaining patient (6%) died of cardiac arrest within 24h. No major bleeding complication was observed. Sixteen patients survived and remained stable for 34±16 (range 11-52) days until hospital discharge. CONCLUSION: Recent surgery is not an absolute contraindication to systemic thrombolysis. Further, to obtain a successful outcome, it is crucial to exclude patients who have received neurosurgical operations or those with other contraindications to thrombolytic therapy.