Am. J. Respir. Crit. Care Med., Volume 159, Number 5, May 1999, 1644-1652

Chemotactic Gradients Predict Neutrophilic Alveolitis in Endotoxin-treated Rats

TIMOTHY S. BLACKWELL, LISA H. LANCASTER, THOMAS R. BLACKWELL, ANNAPURNA VENKATAKRISHNAN, and JOHN W. CHRISTMAN

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine; and The Department of Veterans Affairs Medical Center, Nashville, Tennessee

We hypothesized that the intensity of neutrophilic alveolitis is related to establishing a gradient of neutrophil attractant chemokines across the alveolar-capillary barrier. In these experiments, a positive chemokine gradient toward the alveoli was induced by intratracheal instillation of endotoxin in rats (IT LPS). Alteration of the chemotactic gradient was induced by combining IT LPS (0.1 mg/kg) with an intraperitoneal injection of endotoxin (IP LPS, 6.0 mg/kg). Bronchoalveolar lavage (BAL) and peripheral blood cell counts and differentials, and lavage and serum CXC chemokines were measured 4 h after LPS treatment. Compared with IT LPS treatment alone, IP + IT LPS resulted in a 30-fold reduction in neutrophil (PMN) count in BAL and a decreased percentage of PMNs in lavage (from 82 to 24%, p < 0.01). Total lung myeloperoxidase activity, a reflection of total PMN burden, was increased in all three treatment groups compared with the control group, but differences were not apparent between treatment groups. For the rat CXC chemokines MIP-2 and CINC, high concentrations were detected in BAL from both IT and IP + IT LPS groups; however, significantly higher concentrations were found in the sera of rats treated with IP + IT LPS compared with IT LPS alone. The calculated chemokine BAL-serum gradients were significantly higher for both MIP-2 and CINC in the IT LPS group than in the IT + IP LPS or IP LPS group, and correlated with neutrophil influx into the alveolar spaces 4 h after LPS treatment. In addition, the BAL-serum MIP-2 gradient was found to be increased 24 h after IP LPS, which is the time point of peak neutrophilic alveolitis. In summary, these data show that local chemokine gradients predict the intensity of neutrophilic alveolitis after treatment with endotoxin. Interventions to limit neutrophilic alveolitis could either be targeted to block local lung chemokine production or, paradoxically, to increase systemic production of chemokines.

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