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Bacteria Challenge in Smoke-exposed Mice Exacerbates Inflammation and Skews the Inflammatory Profile

¹ Medical Sciences Graduate Program, ² Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, and ⁵ Department of Medicine, McMaster University, Hamilton, Ontario, Canada; ³ AstraZeneca, Lund, Sweden; and ⁴ Department of Medicine, University at Buffalo, State University of New York, Buffalo, New York

Correspondence and requests for reprints should be addressed to Martin Stämpfli, Ph.D., Department of Pathology and Molecular Medicine, McMaster University, 1200 Main St. West, Hamilton, ON, L8N 3Z5. E-mail: stampfli{at}mcmaster.ca

Rationale: The pathogenesis of chronic obstructive pulmonary disease is associated with acute episodes of bacterial exacerbations. The most commonly isolated bacteria during episodes of exacerbation is nontypeable Haemophilus influenzae (NTHI).

Objectives: In this study, we investigated the in vivo consequences of cigarette smoke exposure on the inflammatory response to an NTHI challenge.

Methods: C57BL/6 and BALB/c mice were exposed to cigarette smoke for 8 weeks and subsequently challenged intranasally with NTHI.

Measurements and Main Results: We observed increased pulmonary inflammation and lung damage in cigarette smoke–exposed NTHI-challenged mice as compared with control NTHI-challenged mice. Furthermore, although NTHI challenge in control mice was marked by increases in tumor necrosis factor-, IL-6, MIP-2, and KC/GRO, NTHI challenge in cigarette smoke–exposed mice led to a prominent up-regulation of a different subset of inflammatory mediators, most notably MCP-1, -3, and -5, IP-10, and MIP-1. This skewed inflammatory mediator expression was also observed after ex vivo NTHI stimulation of alveolar macrophages, signifying their importance to this altered response. Importantly, corticosteroids attenuated inflammation after NTHI challenge in both cigarette smoke–exposed and control mice; however, this was associated with significantly increased bacterial burden.

Conclusions: Collectively, these data suggest that cigarette smoke exacerbates the inflammatory response to a bacterial challenge via skewed inflammatory mediator expression.

Key Words: chronic obstructive pulmonary disease • exacerbation • nontypeable Haemophilus influenzae • mouse model

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject A detailed understanding of the nature of the inflammatory changes during acute exacerbations of chronic obstructive pulmonary disease (COPD) has been difficult to elucidate, as there are limited experimental models due to the clinical and pathological complexity of the underlying disease. What This Study Adds to the Field We show that cigarette smoke exacerbates the inflammatory response to nontypeable Haemophilus influenzae (NTHI) challenge in mice via skewed inflammatory mediator expression. As NTHI is the most frequently isolated bacterial agent during COPD exacerbations, these findings may indicate that exacerbations are associated with underlying alterations of inflammatory pathways.

 

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