Idiopathic pulmonary fibrosis (IPF) is a fatal disease with incompletely understood aetiology and limited treatment options. Traditionally, IPF was believed to be mainly caused by repetitive injuries ...to the alveolar epithelium. Several recent lines of evidence, however, suggest that IPF equally involves an aberrant airway epithelial response, which contributes significantly to disease development and progression. In this review, based on recent clinical, high-resolution imaging, genetic, and single-cell RNA sequencing data, we summarize alterations in airway structure, function, and cell type composition in IPF. We furthermore give a comprehensive overview on the genetic and mechanistic evidence pointing towards an essential role of airway epithelial cells in IPF pathogenesis and describe potentially implicated aberrant epithelial signalling pathways and regulation mechanisms in this context. The collected evidence argues for the investigation of possible therapeutic avenues targeting these processes, which thus represent important future directions of research.
Rationale
Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including ...peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively.
Methods
Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing
Renilla
luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing
Renilla
luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication.
Results
Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model.
Conclusion
The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.
Chronic obstructive pulmonary disease (COPD) collectively refers to chronic and progressive lung diseases that cause irreversible limitations in airflow. Patients with COPD are at high risk for ...severe respiratory symptoms upon influenza virus infection. Airway epithelial cells provide the first-line antiviral defense, but whether or not their susceptibility and response to influenza virus infection changes in COPD have not been elucidated. Therefore, this study aimed to compare the susceptibility of COPD- and control-derived airway epithelium to the influenza virus and assess protein changes during influenza virus infection by quantitative proteomics.
The presence of human- and avian-type influenza A virus receptor was assessed in control and COPD lung sections as well as in fully differentiated primary human bronchial epithelial cells (phBECs) by lectin- or antibody-based histochemical staining. PhBECs were from COPD lungs, including cells from moderate- and severe-stage diseases, and from age-, sex-, smoking, and history-matched control lung specimens. Protein profiles pre- and post-influenza virus infection
were directly compared using quantitative proteomics, and selected findings were validated by qRT-PCR and immunoblotting.
The human-type influenza receptor was more abundant in human airways than the avian-type influenza receptor, a property that was retained
when differentiating phBECs at the air-liquid interface. Proteomics of phBECs pre- and post-influenza A virus infection with A/Puerto Rico/8/34 (PR8) revealed no significant differences between COPD and control phBECs in terms of flu receptor expression, cell type composition, virus replication, or protein profile pre- and post-infection. Independent of health state, a robust antiviral response to influenza virus infection was observed, as well as upregulation of several novel influenza virus-regulated proteins, including PLSCR1, HLA-F, CMTR1, DTX3L, and SHFL.
COPD- and control-derived phBECs did not differ in cell type composition, susceptibility to influenza virus infection, and proteomes pre- and post-infection. Finally, we identified novel influenza A virus-regulated proteins in bronchial epithelial cells that might serve as potential targets to modulate the pathogenicity of infection and acute exacerbations.
The bronchial epithelium is constantly challenged by inhalative insults including cigarette smoke (CS), a key risk factor for lung disease. In vitro exposure of bronchial epithelial cells using CS ...extract (CSE) is a widespread alternative to whole CS (wCS) exposure. However, CSE exposure protocols vary considerably between studies, precluding direct comparison of applied doses. Moreover, they are rarely validated in terms of physiological response in vivo and the relevance of the findings is often unclear. We tested six different exposure settings in primary human bronchial epithelial cells (phBECs), including five CSE protocols compared with wCS exposure. We quantified cell-delivered dose and directly compared all exposures using expression analysis of 10 well-established smoke-induced genes in bronchial epithelial cells. CSE exposure of phBECs was varied in terms of differentiation state, exposure route, duration of exposure, and dose. Gene expression was assessed by quantitative real-time PCR (qPCR) and Western Blot analysis. Cell type-specific expression of smoke-induced genes was analyzed by immunofluorescent analysis. Three surprisingly dissimilar exposure types, namely, chronic CSE treatment of differentiating phBECs, acute CSE treatment of submerged basal phBECs, and wCS exposure of differentiated phBECs performed best, resulting in significant upregulation of seven (chronic CSE) and six (acute wCS, acute submerged CSE exposure) out of 10 genes. Acute apical or basolateral exposure of differentiated phBECs with CSE was much less effective despite similar doses used. Our findings provide guidance for the design of human in vitro CS exposure models in experimental and translational lung research.
Chronic total occlusion (CTO) of coronary artery is a subset where cardiologists confront technical challenges most of the time during percutaneous coronary intervention (PCI). They experience an ...additional impediment when CTO intervention is performed in presence of anomalous coronary artery. Here we report a 58 years old gentleman with Diabetes mellitus and hypertension who admitted with Canadian Cardiovascular Society class III angina for 5 months. Coronary angiography revealed dual vessel coronary artery disease with CTO of right coronary artery (RCA) originating from left sinus of Valsalva. PCI with stenting has been done successfully to RCA lesion. Patient got relieved of angina after PCI and remains stable clinically since then.
Symptomatic bradycardia attributed by sick sinus syndrome in hypertrophic cardiomyopathy (HCM) is not commonly seen. Dual chamber pacing with right ventricular apical lead placement is conventional ...strategy in such scenario. Now physiological pacing which includes left bundle branch (LBB) pacing emerging as new technology for pacemaker implantation. Use of this technique is difficult in HCM due to septal hypertrophy. There is no such case reported so far in the literature where LBB pacing was performed in adult HCM for sick sinus syndrome. Here we present a novel approach of treating irreversible, symptomatic sinus node dysfunction in non-obstructive HCM with implementation of left bundle pacing strategy. Pacing parameters remain stable after 3 months of follow-up.
BACKGROUNDClinical trials that evaluated long-term clinical outcomes of thrombus aspiration before primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial ...infarction (STEMI) have shown different results. Thus, this study was designed to evaluate the long-term clinical outcomes and trends in present usage of thrombosuction in STEMI patients undergoing primary PCI. METHODSThis was a single-center, retrospective study conducted at a tertiary-care center in India between January 2016 and December 2018. A total of 241 patients with STEMI who underwent primary PCI were differentiated into thrombus aspiration or standard primary PCI group. Primary endpoint was major adverse cardiac events (MACE) at 1-year. The other safety outcome measured at 1-year follow-up was stent thrombosis. RESULTSAmong 241 patients, 119 patients were included in the thrombus aspiration group and 122 patients were included in the standard primary PCI group. All patients underwent 1-year follow-up. MACE rate was found to be 4.2% and 4.9% in thrombus aspiration and standard primary PCI group (P=0.79), respectively. Death from any cause was found to be higher in thrombus aspiration 7 (5.9%) compared to standard primary PCI group 5 (4.1%). Of which, cardiac death has occurred in 5 (4.2%) patients of thrombus aspiration group and 4 (3.3%) patients of standard primary PCI group (P=0.747). Definite stent thrombosis was observed in 1 (0.8%) patient of both the groups (P=1.00). CONCLUSIONThe study concludes that there was no significant benefit of thrombus aspiration concerning mortality rate or any other clinical outcomes at 1-year in STEMI patients.
Bradyarrhythmias, characterized by heart rates of <60 bpm due to conduction issues, carry risks of sudden cardiac death and falls. Pacemaker implantation is a standard treatment, but the interplay ...between bradyarrhythmias, coronary artery disease (CAD), and patient attributes requires further exploration. This study was a retrospective hospital record-based study that analyzed data from 699 patients who underwent pacemaker implantation for symptomatic bradyarrhythmias between February 2019 and February 2022. Clinical parameters, coronary angiography (CAG) findings, ejection fraction, and indications for pacemaker implantation were documented. The relationship between CAD severity, specific bradyarrhythmias, and ejection fraction was explored. Statistical analysis included chi-squared tests and t tests. The mean age of the study population (n = 699) was 66.75 years (male:female ratio, 70:30), with 77.2% having type 2 diabetes and 61.6% being hypertensive. The majority of patients had minor or non-obstructive CAD (61.8%), followed by normal CAG findings (25.75%) and obstructive CAD (12.45%). Complete heart block (CHB) was the primary indication for pacemaker implantation (55.2%), followed by sick sinus syndrome (22.3%). The results did not show any association between ejection fraction and CAG findings. Patients who presented with CHB had a higher incidence of obstructive CAD, indicating greater severity. This study sheds light on the intricate interplay between severe bradyarrhythmias, CAD, and patient characteristics. Our analysis revealed no statistical significance between obstructive CAD and the need for a permanent pacemaker. This makes us question our practice of maintaining a low threshold for coronary angiography during pacemaker implantation. The observed low yield and anticoagulation protocol reassure us of the choice to delay this diagnostic intervention. These insights can guide tailored management strategies, enhancing clinical care approaches for patients with severe bradyarrhythmias necessitating pacemaker implantation.Bradyarrhythmias, characterized by heart rates of <60 bpm due to conduction issues, carry risks of sudden cardiac death and falls. Pacemaker implantation is a standard treatment, but the interplay between bradyarrhythmias, coronary artery disease (CAD), and patient attributes requires further exploration. This study was a retrospective hospital record-based study that analyzed data from 699 patients who underwent pacemaker implantation for symptomatic bradyarrhythmias between February 2019 and February 2022. Clinical parameters, coronary angiography (CAG) findings, ejection fraction, and indications for pacemaker implantation were documented. The relationship between CAD severity, specific bradyarrhythmias, and ejection fraction was explored. Statistical analysis included chi-squared tests and t tests. The mean age of the study population (n = 699) was 66.75 years (male:female ratio, 70:30), with 77.2% having type 2 diabetes and 61.6% being hypertensive. The majority of patients had minor or non-obstructive CAD (61.8%), followed by normal CAG findings (25.75%) and obstructive CAD (12.45%). Complete heart block (CHB) was the primary indication for pacemaker implantation (55.2%), followed by sick sinus syndrome (22.3%). The results did not show any association between ejection fraction and CAG findings. Patients who presented with CHB had a higher incidence of obstructive CAD, indicating greater severity. This study sheds light on the intricate interplay between severe bradyarrhythmias, CAD, and patient characteristics. Our analysis revealed no statistical significance between obstructive CAD and the need for a permanent pacemaker. This makes us question our practice of maintaining a low threshold for coronary angiography during pacemaker implantation. The observed low yield and anticoagulation protocol reassure us of the choice to delay this diagnostic intervention. These insights can guide tailored management strategies, enhancing clinical care approaches for patients with severe bradyarrhythmias necessitating pacemaker implantation.
PDF
