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

Abstract

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.

• Authors: Bradley W Richmond, Rui-Hong Du, Wei Han, John T Benjamin, Riet van der Meer, Linda Gleaves, Marshall Guo, Austin McKissack, Yongqin Zhang, Dong-Sheng Cheng, Vasiliy V Polosukhin, Timothy S Blackwell
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 58 Issue 6 Pg. 736-744 (06 2018) ISSN: 1535-4989 [Electronic] United States
• PMID: 29314863 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Aminopyridines
• Benzamides
• Cyclopropanes
• Oscar protein, mouse
• Receptors, Cell Surface
• Roflumilast

Topics

• Airway Remodeling (drug effects, physiology)
• Aminopyridines (pharmacology)
• Animals
• Bacillus (pathogenicity)
• Benzamides (pharmacology)
• Cyclopropanes (pharmacology)
• Disease Models, Animal
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Neutrophils (microbiology, pathology)
• Pneumonia, Bacterial (pathology)
• Pulmonary Disease, Chronic Obstructive (drug therapy, etiology)
• Pulmonary Emphysema (pathology)
• Receptors, Cell Surface (genetics)