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Expression profiling suggests loss of surface integrity and failure of regenerative repair as major driving forces for COPD progression

ABSTRACT: Chronic Obstructive Pulmonary Disease poses a major risk for public health, yet remarkably little is known about its detailed pathophysiology. Definition of COPD as non-reversible pulmonary obstruction may thus reveal more about the spatial orientation of the disease than about its mechanisms. We conducted a controlled observational study allowing for simultaneous assessment of clinical and biological development in COPD. 16 healthy controls and 104 subjects with chronic bronchitis, with or without pulmonary obstruction at baseline, were investigated using both extent and change of bronchial obstruction as main scoring criteria for the analysis of gene expression in lung tissue. We identified 410 genes significantly associated with progression of COPD. 110 of these genes demonstrated a distinctive expression pattern, their functional annotations indicating a participation in the regulation of cellular coherence, membrane integrity, growth and differentiation as well as inflammation and fibroproliferative repair. The regulatory pattern indicates a sequentially unfolding pathology that centers on a two-step failure of surface integrity commencing with a loss of epithelial coherence as early as chronic bronchitis. Decline of regenerative repair starting in GOLD stage I then activates degradation of ECM hyaluronan causing structural failure of the bronchial wall only to be resolved by scar formation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162635 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:Chronic obstructive pulmonary disease (COPD) is diagnosed by airway obstruction and underlies a group of ailments such as bronchitis, emphysema and often asthma; however, rodent models do not resemble human pathology. Because genetically predisposed spontaneously hypertensive (SH) rats display phenotypes such as systemic inflammation, thrombosis, oxidative stress, and suppressed immune function, that are also apparent in COPD patients, we exposed SH and commonly used male Sprague Dawley (SD) to 0, 250, or 350 ppm sulfur dioxide (SO2), 5h/d for 4 consecutive days. Airways disease was characterized by pulmonary functional, pathological and molecular analysis. SO2 caused dose-dependent changes in breathing parameters in both strains with SH rats being slightly more affected than SD. Bronchoalveolar lavage fluid (BALF) total cells and neutrophilic inflammation were dose-dependent and significantly greater in SH than in SD rats. The recovery was incomplete 4-day following SO2 exposure in SH rats. Pulmonary protein leakage did not occur in either strain but lactate dehydrogenase and n-acetyl glucosaminidase activity was increased in BALF of SH rats. Lung pathology and morphometric evaluation of mucin production in the airways demonstrated significantly greater impact of SO2 in SH than in SD rats. Baseline differences in lung gene expression pattern suggested marked immune dysregulation, oxidative stress, and impairment cell signaling and fatty acid metabolism in SH rats. Gene expression pattern of SD and SH rats following SO2 exposure demonstrated greater effect on inflammation/immune markers, and oxidative stress. Thus, the SH rat may serve as a better and more susceptible rat strain to be used for experimental model of bronchitis which is relevant to human disease. Experiment Overall Design: Spontaneously hypertensive and Sprague Dawley rats were used in this experiment. Each strain of rat was treated with either SO2 or AIR (control). There were 4 biological replicates for each strain/treatment.

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Expression profiling suggests loss of surface integrity and failure of regenerative repair as major driving forces for COPD progression

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