INTRATRACHEAL ADMINISTRATION OF ENDOTOXIN AND CYTOKINES .6. ANTISERUMTO CINC INHIBITS ACUTE-INFLAMMATION

Cytokine-induced neutrophil chemoattractant (CINC), a chemotactic mole cule of the interleukin (IL)-8 family, is known to be induced in the r at in response to tumor necrosis factor (TNF), IL-1, and lipopolysacch aride (LPS). Intratracheal injection of endotoxin (LPS) is shown to ca use CINC mRNA expression in pulmonary tissue, peaking after 2 h, and C INC protein expression in bronchoalveolar lavage (BAL) fluid, peaking after 2-4 h. Intratracheal injection of synthetic CINC causes acute in flammation that is abrogated by coinjection of antiserum to purified n atural rat CINC. Intratracheal injection of antiserum to CINC inhibits intratracheal LPS- and IL-1-induced neutrophil emigration into BAL fl uid by similar to 60-70%. Despite the anti-inflammatory activity of an ti-CINC antiserum, TNF is elevated in the lavage fluid of rats receivi ng anti-CINC, suggesting that CINC may act in a negative feedback loop to downregulate TNF expression. Intratracheal injection of antiserum to CINC combined with intravenous injection of anti-E-selectin antibod y inhibits intratracheal LPS- and IL-1-induced neutrophil emigration i nto BAL fluid by similar to 75-85%. CINC-mediated chemotactic activity and E-selectin-mediated adherence of neutrophils to endothelium contr ibute significantly to the pathogenesis of LPS-initiated acute inflamm ation.