The role of the CC chemokines, macrophage inflammatory protein-1β (MIP-1β), monocyte chemotactic peptide-1 (MCP-1), and RANTES, in acute lung inflammatory injury induced by intrapulmonary deposition of IgG immune complexes injury in rats was determined. Rat MIP-1β, MCP-1, and RANTES were cloned, the proteins were expressed, and neutralizing Abs were developed. mRNA and protein expression for MIP-1β and MCP-1 were up-regulated during the inflammatory response, while mRNA and protein expression for RANTES were constitutive and unchanged during the inflammatory response. Treatment of rats with anti-MIP-1β Ab significantly decreased vascular permeability by 37% (p = 0.012), reduced neutrophil recruitment into lung by 65% (p = 0.047), and suppressed levels of TNF-α in bronchoalveolar lavage fluids by 61% (p = 0.008). Treatment of rats with anti-rat MCP-1 or anti-rat RANTES had no effect on the development of lung injury. In animals pretreated intratracheally with blocking Abs to MCP-1, RANTES, or MIP-1β, significant reductions in the bronchoalveolar lavage content of these chemokines occurred, suggesting that these Abs had reached their targets. Conversely, exogenously MIP-1β, but not RANTES or MCP-1, caused enhancement of the lung vascular leak. These data indicate that MIP-1β, but not MCP-1 or RANTES, 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.

We have examined the role of IL-18 after acute lung inflammation in rats caused by intrapulmonary deposition of IgG immune complexes. Constitutive IL-18 mRNA and protein expression (precursor form, 26 kDa) were found in normal rat lung, whereas in inflamed lungs, IL-18 mRNA was up-regulated; in bronchoalveolar (BAL) fluids, the 26-kDa protein form of IL-18 was increased at 2–4 h in inflamed lungs and remained elevated at 24 h, and the “mature” protein form of IL-18 (18 kDa) appeared in BAL fluids 1–8 h after onset of inflammation. ELISA studies confirmed induction of IL-18 in inflamed lungs (in lung homogenates and in BAL fluids). Prominent immunostaining for IL-18 was found in alveolar macrophages from inflamed lungs. When rat lung macrophages, fibroblasts, type II cells, and endothelial cells were cultured in vitro with LPS, only the first two produced IL-18. Intratracheal administration of rat recombinant IL-18 in the lung model caused significant increases in lung vascular permeability and in BAL content of neutrophils and in BAL content of TNF-α, IL-1β, and cytokine-induced neutrophil chemoattractant, whereas intratracheal instillation of anti-IL-18 greatly reduced these changes and prevented increases in BAL content of IFN-γ. Intratracheal administration of the natural antagonist of IL-18, IL-18 binding protein, resulted in suppressed lung vascular permeability and decreased BAL content of neutrophils, cytokines, and chemokines. These findings suggest that endogenous IL-18 functions as a proinflammatory cytokine in this model of acute lung inflammation, serving as an autocrine activator to bring about expression of other inflammatory mediators.

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This study was initiated to determine the effect of physical exercise on the in vivo tumor necrosis factor-alpha (TNF) response to Escherichia coli lipopolysaccharide (LPS). Rats familiarized with treadmill running and surgically implanted with vascular catheters were either not exercised or exercised to near exhaustion (mean run time of 102 +/- 13 min) before intravenous LPS challenge (1 mg/kg; lethality of dose is 10-20% in 24 h). Compared with time-matched nonexercised control rats, exercised rats had increased heart rates, plasma lactate, and plasma corticosterone and decreased plasma glucose at the conclusion of exercise. In response to LPS, both groups became hypotensive, exhibited transient hyperglycemia, and sustained hyperlactacidemia. By 30 min post-LPS, plasma corticosterone levels were similar in the two groups. Nonexercised rats exhibited a normal plasma TNF response to LPS with the peak value (10,400 +/- 2,000 U/ml) occurring 90 min after LPS challenge. In contrast, the TNF response in rats exercised before LPS administration was blunted to 17% of the nonexercised group, with the peak occurring at an earlier time after LPS. Addition of recombinant murine TNF to postexercise plasma was fully expressed. The TNF response remained attenuated when LPS was administered up to 6 h after completion of exercise, but it returned to normal in rats allowed to recover for 24 h. The results demonstrate that exercise, perhaps as a stress modality, markedly suppresses the systemic TNF response that is normally observed in response to LPS challenge.