Angiotensin-converting enzyme 2 in peripheral lung club cells modulates the susceptibility to SARS-CoV-2 in chronic obstructive pulmonary disease.

Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.

Mucus Hypersecretion and Ciliary Impairment in Conducting Airway Contribute to Alveolar Mucus Plugging in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease attributed to the complex interplay of genetic and environmental risks. The muco-ciliary clearance (MCC) system plays a critical role in maintaining the conduit for air to and from the alveoli, but it remains poorly understood whether the MCC abnormalities in conducting airway are involved in IPF pathogenesis. In this study, we obtained the surgically resected bronchi and peripheral lung tissues from 31 IPF patients and 39 control subjects, and we sought to explore the morphologic characteristics of MCC in conducting airway by using immunostaining and scanning and transmission electron microscopy. In the submucosal regions of the bronchi, we found that the areas of mucus glands (MUC5B+) were significantly larger in IPF patients as compared with control subjects (p < 0.05). In the surface epithelium of three airway regions (bronchi, proximal bronchioles, and distal bronchioles), increased MUC5B and MUC5AC expression of secretory cells, decreased number of ciliated cells, and increased ciliary length were observed in IPF patients than control subjects (all p < 0.05). In addition, the mRNA expression levels of MUC5B were up-regulated in both the bronchi and peripheral lung of IPF patients than those of control subjects (p < 0.05), accompanied with 93.55% IPF subjects who had obvious MUC5B+ mucus plugs in alveolar regions. No MUC5B rs35705950 single-nucleotide polymorphism allele was detected in both IPF patients and control subjects. Our study shows that mucus hypersecretion and ciliary impairment in conducting airway are major causes of mucus plugs in alveolar regions and may be closely related to the alveolar injuries in IPF patients.

Aberrant Epithelial Cell Proliferation in Peripheral Airways in Bronchiectasis.

Dilation of bronchi and bronchioles caused by destruction and excessive epithelial remodeling is a characteristic feature of bronchiectasis. It is not known how epithelial progenitor cells contribute to these pathologic conditions in peripheral airways (bronchioles) in bronchiectasis. We aimed to explore the expression levels of signature airway progenitor cells in the dilated bronchioles in patients with bronchiectasis. We obtained the surgically resected peripheral lung tissues from 43 patients with bronchiectasis and 33 control subjects. Immunostaining was performed to determine the expression patterns of thyroid transcription factor-1 (TTF-1, for labeling progenitor cells in distal airways), P63 (basal cells), club cell 10 kDa protein (CC10, club cells), and surfactant protein C (SPC, alveolar type II epithelial cells) in epithelium or sub-epithelium. Here, we reported significantly lower percentage of TTF-1+ cells and CC10+ cells, and higher percentage of P63+ cells within the epithelium of dilated bronchioles compared with control bronchioles. In airway sub-epithelium of the dilated bronchioles, epithelial hyperplasia with disarrangement of TTF-1+ cells yielded cuboidal (100%) and columnar (93.0%) type among bronchiectasis patients. Most progenitor cell markers co-localized with TTF-1. The median (the 1st, 3rd quartile) percentage of P63+TTF-1+, CC10+TTF-1+, and SPC+TTF-1+ cells was 16.0% (8.9, 24.0%), 14.5% (7.1, 20.8%), and 52% (40.3, 64.4%), respectively. For cuboidal epithelial hyperplasia, 91.0% (86.5, 94.0%) of areas co-stained with SPC and TTF-1. Columnar epithelial hyperplasia was characterized by TTF-1 co-staining with P63+TTF-1+ and CC10+TTF-1+ cells. Taken together, aberrant proliferation of airway progenitor cells in both epithelium and sub-epithelium are implicated in bronchiectasis.