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Background and objective: COVID‐19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS‐CoV‐2 that requires the ACE2 receptor and serine proteases to enter AEC. We determined what factors are associated with ACE2 expression particularly in patients with asthma and COPD. Methods: We obtained lower AEC from 145 people from two independent cohorts, aged 2–89 years, Newcastle (n = 115) and Perth (n = 30), Australia. The Newcastle cohort was enriched with people with asthma (n = 37) and COPD (n = 38). Gene expression for ACE2 and other genes potentially associated with SARS‐CoV‐2 cell entry was assessed by qPCR, and protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AEC. Results: Increased gene expression of ACE2 was associated with older age (P = 0.03) and male sex (P = 0.03), but not with pack‐years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma patients (P = 0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in patients with asthma (P = 0.02), while ADAM‐17, a disintegrin that cleaves ACE2 from the surface, was increased (P = 0.02). ACE2 protein expression was also reduced in endobronchial biopsies from asthma patients. Conclusion: Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over‐represented in those with COVID‐19 complications. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective The objective of this study was to enumerate total cells and the number of inflammatory cell differentials in large airways ( LAs) versus small airways ( SAs) of mild-moderate COPD, and against appropriate controls. Methods For LA, we used endobronchial biopsies and for SA resected lung tissues. Immunostaining was enumerated (cells per mm2) for macrophages, neutrophils, CD4 and CD8 T cells in the lamina propria ( LP) up to 150 µM deep for LA and full wall thickness for SA. Results We confirmed hypocellularity in the LA and in the SA wall in smokers and COPD ( P < 0.001). LA cellularity was least in current smokers with COPD ( COPD-CS) ( P < 0.01), while SA cellularity was similar across smoker/ COPD groups. LA neutrophils were decreased in COPD-CS ( P < 0.01), while SA neutrophil counts were unchanged. Compared with controls, LA macrophage numbers in COPD were significantly lower ( P < 0.05), with SA macrophage numbers unchanged. A significant increase was observed in SA CD8+ cells in both normal smokers ( P < 0.01) and COPD-CS ( P < 0.001) but not in LA. Conclusion These unique data indicate that the current model for airway wall inflammation in COPD is oversimplified, and contrast with innate inflammatory activation in the lumen, at least in mild-moderate disease. Any abnormalities in airway wall cell differentials are small, although exaggerated in percentage terms. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective COPD is characterized by poorly reversible airflow obstruction usually due to cigarette smoking. Transforming growth factor ( TGF)-β1 has been implicated in the pathogenesis of COPD, and in particular a process called epithelial mesenchymal transition ( EMT), which may well be an intermediatory between smoking and both airway fibrosis and lung cancer. The downstream classical or 'canonical' TGF-β1 pathway is via the phosphorylated (p) Smad transcription factor system. Methods We have investigated TGF-β1 expression and its ' pSmad fingerprint' in bronchoscopic airway biopsies from patients with COPD, and in smoking and non-smoking controls. A cross-sectional immunohistochemical study compared TGF-β1 and pSmad 2, 3 (excitatory) and 7 (inhibitory) expression in cells and blood vessels of three compartments of large airways: epithelium (especially the basal region), reticular basement membrane (Rbm) and underlying lamina propria ( LP). Results TGF-β1 expression was generally higher in COPD subjects throughout the airway wall ( P < 0.01), while pSmad 2/3 expression was associated with smoking especially in current smoking COPD ( P < 0.05). Expression of inhibitory pSmad 7 was also prominently reduced in patients with COPD in contrast to smokers and controls ( P < 0.01). In addition, pSmad, but not TGF-β1 expression, was related to airflow obstruction and a canonical EMT biomarker ( S100 A4) expression. Conclusion Activation of the Smad pathway in the airways is linked to EMT activity and loss of lung function. The disconnection between TGF-β1 and pSmad in terms of relationships to EMT activity and lung function suggests that factors other than or in addition to TGF-β1 are driving the process. [ABSTRACT FROM AUTHOR]

Soltani A, Muller H K, Sohal S S, Reid D W, Weston S, Wood-Baker R & Walters E H (2012) Histopathology 60, 964-970 Distinctive characteristics of bronchial reticular basement membrane and vessel remodelling in chronic obstructive pulmonary disease (COPD) and in asthma: they are not the same disease Aims: This study compared reticular basement membrane (Rbm) and vascular remodelling within the bronchial mucosa of subjects with chronic obstructive pulmonary disease (COPD) with those from patients with asthma, to test the 'Dutch hypothesis' of whether these are essentially the same or different pathological conditions. Methods and results: Bronchoscopic biopsies were stained with anti-collagen IV antibody; 18 current smoking COPD, 10 symptomatic asthmatics and 13 healthy non-smoking controls were studied. The Rbm in COPD was fragmented, non-homogeneous, variable in thickness and hypervascular, whereas in asthma the Rbm was compact and homogeneous with no evidence of increased vascularity compared to controls. Length of Rbm splitting presented as percentage of Rbm length was used to measure fragmentation; it was greater in COPD than in controls and asthmatics [median (range) 20.7% (0.4-68.5) versus 5.3% (0.0-21.7) versus 1.5% (0.0-15.1), P < 0.001]. The number of Rbm vessels/mm Rbm [median (range) 10.1 (1.6-23.0) versus 4.5 (0.0-26.4) versus 4.4 (0.4-8.1), P < 0.01] and area of Rbm vessels, μm2/mm Rbm [median (range) 953 (115-2456) versus 462 (0-3263) versus 426 (32-2216), P < 0.05] was also increased in COPD compared to normal subjects and asthmatics. Conclusions: The characteristics of Rbm remodelling are quite different in asthma and COPD. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective: In COPD, the airways are chronically inflamed, and we have now observed fragmentation of the reticular basement membrane (Rbm). This appears to be a hallmark of the process known as epithelial mesenchymal transition (EMT), in which epithelial cells migrate through the Rbm and differentiate into fibroblasts. The aim of this study was to confirm the extent and relevance of Rbm fragmentation in smokers and patients with COPD, and to undertake a preliminary analysis of some classical markers of EMT. Methods: Endobronchial biopsies from current smokers (CS; n = 17) and ex-smokers with COPD (ES; n = 15), smokers with normal lung function (NS; n = 16) and never-smoking control subjects (NC; n = 15) were stained for the EMT markers, S100A4, vimentin, epidermal growth factor receptor and matrix metalloproteinase-9. Results: Compared with NC, there was significant Rbm fragmentation in the CS, ES and NS groups, which was positively associated with smoking history in subjects with COPD. Staining for basal epithelial S100A4, epithelial epidermal growth factor receptor and matrix metalloproteinase-9 in cells within Rbm clefts, and for S100A4 in Rbm cells, was increased in the CS, NS and ES groups compared with the NC group. There was also increased Rbm cell S100A4 staining in the CS group compared with the ES and NS groups. Basal epithelial cell staining for S100A4 was inversely correlated with airflow limitation. Double staining for both S100A4 and vimentin further strengthened the likelihood that these changes represented active EMT. Conclusions: This is the first detailed description of fragmentation and cellularity of the Rbm in smokers, which were most marked in subjects with COPD. The data are consistent with active EMT in these subjects. [ABSTRACT FROM AUTHOR]