Effects of systemic and local CXC chemokine administration on the ethanol-induced suppression of pulmonary neutrophil recruitment.
BACKGROUND
Acute alcohol intoxication impairs the neutrophil response to intrapulmonary infection, resulting in impaired host defense and increased patient morbidity and mortality. We recently showed that intratracheal (IT) chemokine administration promotes pulmonary neutrophil migration in rats and that this process is enhanced by systemic administration of the Glu-Leu-Arg (ELR+) and CXC chemokine cytokine-induced neutrophil chemoattractant (CINC). Here we hypothesized that exogenous chemokine administration would mitigate the suppressive effect of alcohol on neutrophil recruitment into the lung.


METHODS
Macrophage inflammatory protein-2 (MIP-2), a rat ELR+ CXC chemokine, or live Klebsiella pneumoniae (K. pneumoniae) was administered it to induce alveolar neutrophil migration in the absence or presence of acute ethanol intoxication. Depending on the experimental protocol, rats received either intravenous (IV) CINC or IT chemokines (CINC and MIP-2) 20 min after it MIP-2 or K. pneumoniae. Rats were euthanized 90 min or four hr after the first IT injection for sample collection.


RESULTS
Neutrophil counts were significantly elevated in bronchoalveolar lavage fluid (BALF) of rats receiving IT MIP-2 compared with vehicle-treated rats, and this response was significantly decreased in animals pretreated with ethanol. CINC IV enhanced the neutrophil response to IT MIP-2 in both the absence and presence of acute ethanol intoxication. In rats challenged with K. pneumoniae, ethanol pretreatment significantly reduced BALF levels of CINC and MIP-2, suppressed alveolar neutrophil recruitment, and decreased whole-lung myeloperoxidase activity. CINC IV did not alter BALF neutrophil counts in the absence or presence of ethanol administration 4 hr after IT K. pneumoniae. Alternatively, IT chemokine instillation partially restored BALF neutrophil recruitment but not whole-lung myeloperoxidase activity in ethanol-treated rats.


CONCLUSIONS
Ethanol significantly inhibits the pulmonary inflammatory responses to both MIP-2 and K. pneumoniae. Exogenous chemokine administration may be a useful means to enhance host defenses in the ethanol-intoxicated host, although the results of this study also indicate that ethanol intoxication can impair neutrophil recruitment, independent of its effects on local chemotactic gradients.
Quinton
Lee J
LJ
Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Nelson
Steve
S
Zhang
Ping
P
Happel
Kyle I
KI
Gamble
Lisa
L
Bagby
Gregory J
GJ
D000435:Alcoholic Intoxication / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D007108:Immune Tolerance / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000494:pharmacology*; D007710:Klebsiella Infections / Q000276:immunology*; D007711:Klebsiella pneumoniae / Q000276:immunology*; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000097:blood / Q000494:pharmacology*; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology
D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins; D000431:Ethanol; D009195:Peroxidase