Cigarette Smoke Impairs Innate Host Defense Against Pneumoccal Pneumonia.

Abstract

Exposure to cigarette smoke (CS) is associated with increased risk of many infectious diseases including those caused by Streptococcus pneumoniae. Such pneumococcal infections are the leading cause of community-acquired pneumonia and deaths from invasive bacterial infections. Since CS exposure also impairs the function of the alveolar macrophage (AM), a cell central to innate host defense in the lung, we used in vivo and in vitro approaches to determine the effects of CS exposure in a murine model of pneumococcal pneumonia, and to elucidate how CS-mediated impairment of AM function might contribute to this relationship. Mice exposed to CS over 5 weeks developed more serious infections, with 4-fold and 35-fold higher pulmonary bacterial burdens at 24 hr and 48 hr post-infection, respectively. In separate experiments, we compared the effects of low-tar versus regular cigarettes on cellular recruitment and AM function, finding no evidence to support the perception that low-tar cigarettes might be less harmful. In vitro, AMs from CS-exposed animals displayed impaired cytokine production following pneumococcal challenge and reduced phagocytosis of bacteria but not IgG-opsonized microspheres, indicating intact FcR-mediated phagocytosis. To remove possible effects from other cells, naive AMs were treated in vitro with cigarette smoke conditioned media (CSCM), yielding similar impairments in phagocytosis that were specific to complement-opsonized pneumococcus, but no impairment in FcR-mediated microsphere phagocytosis. However in another experiment, CSCM-pretreated rat AMs did display impaired phagocytosis of IgG-opsonized E.coli, suggesting CS may interfere with TLR-mediated bacterial recognition. CSCM pretreatment impaired cytokine synthesis and reactive oxygen intermediate generation following challenge with LTA, a bacterial ligand for TLR2. However no differences were seen in TLR2 transcription suggesting that CSCM may impair TLR-mediated AM activation through disruption of downstream reactive oxygen intermediate-mediated signal transduction. Such a mechanism would indicate common themes underlying some of the diverse effects of CS exposure on immune function. Overall, the novel finding of impaired pulmonary innate host defense following CS exposure, and observation of AM bacterial recognition and phagocytosis impairments, may suggest new directions for understanding the effects of CS exposure on human health.