Bacteria challenge in smoke-exposed mice exacerbates inflammation and skews the inflammatory profile

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-α,IL-6, MIP-2, andKC/GROα,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 MI P-1γ. 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 chal-lenge in both cigarette smoke-exposed and controlmice; 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.