Alcohol-Induced Suppression of Lung Chemokine Production and the Host Defense Response to Streptococcus pneumoniae Darren M. Boé, Steve Nelson, Ping Zhang, Lee Quinton, and Gregory J. Bagby Background: Acute alcohol intoxication impairs neutrophil migration in response to intrapulmonary infection with Streptococcus pneumoniae, the most common bacterial cause of pneumonia. Many of the same host defense functions that are impaired in the alcohol-intoxicated host are mechanistically associated with chemokines, a group of proinflammatory molecules that enhance neutrophil adhesion and direct neutrophil migration to sites of inflammation. The purpose of this study was to determine whether alcohol- induced chemokine suppression is responsible for impaired neutrophil recruitment into the lung during infection of the alcohol-intoxicated host. Methods: S. pneumoniae was administered (10 7 colony-forming units) intratracheally 30 min after intraperitoneal injection of 20% alcohol (5.5 g/kg) or saline. Four hours after bacterial challenge, bron- choalveolar lavage fluid (BALF) was collected, and the ability of BALF to induce neutrophil chemotaxis and adhesion molecule expression was measured by using chemotactic and flow cytometric assays. In another experiment, intratracheal challenge was performed by using recombinant macrophage inflamma- tory protein-2 (MIP-2), and BALF neutrophils were measured. Results: BALF MIP-2 and cytokine-induced neutrophil chemoattractant were decreased by alcohol, and BALF from alcohol-intoxicated animals had decreased chemotactic activity for neutrophils, as well as a decreased ability to up-regulate neutrophil adhesion molecule expression, compared with controls. This decreased chemotactic activity was significantly increased in the alcohol group by repletion of chemokines to control levels. Alcohol also suppressed neutrophil recruitment after intrapulmonary challenge with MIP-2, suggesting that mechanisms other than chemokine suppression contribute to the alcohol-induced effect. Conclusions: At least two mechanisms, suppressed chemokine production and impaired neutrophil adhesion molecule expression, likely work in concert in the alcohol-intoxicated host to impair neutrophil adhesion and migration into the lung during pneumococcal infection. These alterations in neutrophil function likely increase the susceptibility of alcohol-consuming hosts to pneumonia. Key Words: Alcohol, MIP-2, CINC, Neutrophils, Chemotaxis. I T HAS LONG been recognized that alcohol abuse in- creases the severity of pneumococcal pneumonia by im- pairing neutrophil migration into the lungs (Pickrell, 1938; Winterbauer et al., 1969). It is interesting to note that alcohol does not directly alter the ability of neutrophils to migrate toward a chemotactic stimulus in vitro until ex- tremely high alcohol concentrations are reached (Hallen- gren and Forsgren, 1978; Spagnuolo and MacGregor, 1975). Thus, it is likely that alcohol acts through alternate mechanisms to impair neutrophil migration during infection. Neutrophil migration from the intravascular compart- ment to the site of infection is a complex process that involves many critical steps. Alcohol has been shown to alter many of these steps, including neutrophil adhesion molecule expression, neutrophil adhesion, and proinflam- matory cytokine production (Hallengren and Forsgren, 1978; Nelson et al., 1989a; Spagnuolo and MacGregor, 1975; Szabo et al., 1996; Zhang et al., 1998). In many cases, these alcohol-induced affects are associated with decreased neutrophil recruitment and suppressed host defense (Nel- son et al., 1989a,b, 1991). Many of the same host-defense functions that are im- paired in the alcohol-intoxicated host are mechanistically associated with chemokines, a group of proinflammatory molecules that enhance neutrophil adhesion and direct neutrophil migration to the sites of inflammation. There- From the Department of Physiology (DMB, LQ, GJB), Department of Medicine—Section of Pulmonary and Critical Care Medicine (SN, PZ), and Alcohol Research Center (DMB, SN, PZ, GJB), Louisiana State University Health Sciences Center, New Orleans, Louisiana. Received for publication April 23, 2003; accepted August 28, 2003. Supported by Public Health Service Grant AA09803. DMB was supported by Institutional National Research Service Award AA07577. Reprint requests: Gregory J. Bagby, PhD, Department of Physiology, LSU Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112; Fax: 504-568-6158; E-mail: gbagby@lsuhsc.edu. Copyright © 2003 by the Research Society on Alcoholism. DOI: 10.1097/01.ALC.0000095634.82310.53 0145-6008/03/2711-1838$03.00/0 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 27, No. 11 November 2003 1838 Alcohol Clin Exp Res, Vol 27, No 11, 2003: pp 1838–1845