Role of CC chemokines (macrophage inflammatory protein-1 beta, monocyte chemoattractant protein-1, RANTES) in acute lung injury in rats

The role of the CC chemokines, macrophage inflammatory protein-1 beta (MIP- 1 beta), monocyte chemotactic peptide-1 (MCP-1), and RANTES, in acute lung inflammatory injury induced by intrapulmonary deposition of IgG immune comp lexes injury in rats was determined. Rat MIP-1 beta, MCP-1, and RANTES were cloned, the proteins were expressed, and neutralizing Abs were developed. mRNA and protein expression for MIP-1 beta and MCP-1 mere up-regulated duri ng the inflammatory response, while mRNA and protein expression for RANTES were constitutive and unchanged during the inflammatory response. Treatment of rats with anti-MIP-1 beta Ab significantly decreased vascular permeabil ity by 37% (p = 0.012), reduced neutrophil recruitment into lung by 65% (p = 0.047), and suppressed levels of TNF-alpha in bronchoalveolar lavage flui ds by 61% (p = 0.008). Treatment of rats with anti-rat MCP-1 or anti-rat RA NTES had no effect on the development of lung injury, In animals pretreated intratracheally with blocking Abs to MCP-1, RANTES, or MIP-1 beta, signifi cant reductions in the bronchoalveolar lavage content of these chemokines o ccurred, suggesting that these Abs had reached their targets. Conversely, e xogenously MIP-1 beta, but not RANTES or MCP-1, caused enhancement of the l ung vascular leak. These data indicate that MIP-1 beta, but not MCP-1 or RA NTES, plays an important role in intrapulmonary recruitment of neutrophils and development of lung injury in the model employed, The findings suggest that in chemokine-dependent inflammatory responses in lung CC chemokines do not necessarily demonstrate redundant function.