Chronic nicotine inhibits inflammation and promotes influenza infection

Abstract

Epidemiological data suggest an association between smoking, respiratory infections, and impaired wound healing. Inflammation is critical in the body’s defense against pathogens and in the wound-healing process. Although nicotine is used to treat some inflammatory conditions, the mechanism of this action is largely unknown. To determine how nicotine affects inflammation, rats and mice were exposed to nicotine via miniosmotic pumps, and the inflammatory response to turpentine or influenza virus was assessed. Results showed that while nicotine suppressed the migration of leukocytes to the inflammation/infection site, it increased the influenza titer in the lung. The decreased inflammation correlated with lower chemotaxis/chemokinesis of peripheral blood mononuclear cells (PBMC) toward formyl-methionyl-leucyl-phenylalanine and monocyte chemoattractant protein-1 without affecting the density of their respective receptors. However, nicotine suppressed the chemokine-induced Ca²⁺ response in PBMC, indicating impaired chemokine signaling. Thus, because nicotine suppresses leukocyte migration, it might contribute to the delayed wound healing and increased incidence of respiratory infections among smokers.

Introduction

Tobacco smoking suppresses the immune system, and smoking is an established risk factor for lung cancer, cardiovascular disease, chronic obstructive pulmonary disease, respiratory infections, and the leading cause of avoidable mortality in industrialized countries [1]. Smokers also show delayed wound repair following injuries and surgery [2], [3], prompting surgeons to advise their patients to stop smoking for a few weeks before and after surgery [4], [5]. Interestingly, smokers have a lower incidence of some inflammatory diseases or diseases with an inflammatory component, such as ulcerative colitis, sarcoidosis, cutaneous inflammation, endometriosis, and Parkinson’s disease [1], [2], [6]. Nicotine (NT), a major constituent of cigarette smoke, has been used to alleviate ulcerative colitis [7], Parkinson’s disease [8], [9], and cutaneous inflammation [10]. The ability of NT to ameliorate some inflammatory diseases suggests that NT might be an anti-inflammatory. Indeed, in a model of turpentine-induced sterile abscess, NT-treated animals exhibited a significantly lower fever response after turpentine injection [11], [12], [13]. Inflammatory responses are critical in controlling infections and the wound-repair process [14], and suppression of inflammation might explain the decreased incidence of some inflammatory diseases, increased wound-healing time, and the increased susceptibility of smokers to infections. However, the mechanism by which NT attenuates the inflammatory response has not been defined. Here, we show that chronic in vivo exposures to NT inhibit leukocyte migration to the inflammation site, and this inhibition correlates with the loss of random and chemoattractant-induced migratory responses of leukocytes. These results demonstrate for the first time that the anti-inflammatory properties of NT result from the altered responsiveness of leukocytes to chemokines, the “traffic controllers” of the immune system.