Bacterial-derived Neutrophilic Inflammation Drives Lung Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease.

Richmond BW, Du RH, Han W, Benjamin JT, van der Meer R, Gleaves L, Guo M, McKissack A, Zhang Y, Cheng DS, Polosukhin VV, Blackwell TS
Am J Respir Cell Mol Biol. 2018 58 (6): 736-744

PMID: 29314863 · PMCID: PMC6002662 · DOI:10.1165/rcmb.2017-0329OC

Loss of secretory IgA is common in the small airways of patients with chronic obstructive pulmonary disease and may contribute to disease pathogenesis. Using mice that lack secretory IgA in the airways due to genetic deficiency of polymeric Ig receptor (pIgR mice), we investigated the role of neutrophils in driving the fibrotic small airway wall remodeling and emphysema that develops spontaneously in these mice. By flow cytometry, we found an increase in the percentage of neutrophils among CD45 cells in the lungs, as well as an increase in total neutrophils, in pIgR mice compared with wild-type controls. This increase in neutrophils in pIgR mice was associated with elastin degradation in the alveolar compartment and around small airways, along with increased collagen deposition in small airway walls. Neutrophil depletion using anti-Ly6G antibodies or treatment with broad-spectrum antibiotics inhibited development of both emphysema and small airway remodeling, suggesting that airway bacteria provide the stimulus for deleterious neutrophilic inflammation in this model. Exogenous bacterial challenge using lysates prepared from pathogenic and nonpathogenic bacteria worsened neutrophilic inflammation and lung remodeling in pIgR mice. This phenotype was abrogated by antiinflammatory therapy with roflumilast. Together, these studies support the concept that disruption of the mucosal immune barrier in small airways contributes to chronic obstructive pulmonary disease progression by allowing bacteria to stimulate chronic neutrophilic inflammation, which, in turn, drives progressive airway wall fibrosis and emphysematous changes in the lung parenchyma.

MeSH Terms (14)

Airway Remodeling Aminopyridines Animals Bacillus Benzamides Cyclopropanes Disease Models, Animal Mice, Inbred C57BL Mice, Mutant Strains Neutrophils Pneumonia, Bacterial Pulmonary Disease, Chronic Obstructive Pulmonary Emphysema Receptors, Cell Surface

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