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Pulmonary Expression of Tumor Necrosis Factor Alpha, Interleukin-1 Beta, and Interleukin-8 in the Acute Phase of Bovine Pneumonic Pasteurellosis

Departments of Clinical and Population Sciences (CM, TRA) and Veterinary PathoBiology (MSA, SKM), College of Veterinary Medicine, University of Minnesota, St. Paul, MN

Inflammatory cytokines are suspected to contribute to the pathogenesis of bovine pneumonic pasteurellosis (BPP) through neutrophil recruitment, leukocyte activation, and the induction of a broad array of soluble inflammatory mediators. An in vivo experimental model of BPP was used to characterize the pulmonary expression kinetics of tumor necrosis factor alpha (TNF), interleukin-1 beta (IL-1ß), and interleukin-8 (IL-8) genes and proteins during the acute phase of disease development. Cytokine expression in bronchoalveolar lavage (BAL) fluid, BAL cells, and pneumonic lung parenchyma was quantitated by northern blot analysis, enzyme-linked immunosorbent assay (ELISA), and in situ hybridization at 2, 4, 8, 16, and 24 hours after endobronchial inoculation of Pasteurella (Mannheimia) haemolytica. Expression of TNF, IL-1ß, and IL-8 was significantly increased in the airways and lung lesions of infected calves as compared with mock-infected controls. Although kinetic patterns varied, peak levels of cytokine mRNA occurred within 8 hours postinfection (PI), and peak cytokine concentrations occurred within 16 hours PI. In all samples, IL-8 was expressed to the greatest extent and TNF was least expressed. Expression of TNF was restricted to alveolar macrophages. Alveolar and interstitial macrophages produced IL-1ß and IL-8 in the first 4 hours; bronchial and bronchiolar epithelial cells were also significant sources of IL-8 during this period. By 8 hours PI, neutrophils were the dominant source of both IL-1ß and IL-8. These findings demonstrate a spatial and temporal association between pulmonary expression of inflammatory cytokines and acute lung pathology, supporting the hypothesis that cytokines contribute to inflammatory lung injury in BPP.

Key words: Cattle; chemokine; enzyme-linked immunosorbent assay; in situ hybridization; morphometric analysis; northern blot; pneumonia; proinflammatory cytokine.

Request reprints from Dr. S. K. Maheswaran, Department of Veterinary PathoBiology, 205 Veterinary Sciences, 1971 Commonwealth Avenue, University of Minnesota, St. Paul, MN 55108 (USA). Email: mahes001{at}tc.umn.edu.

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