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ROLE OF CELL SIGNALING IN PROTECTION FROM DIESEL AND LPS INDUCED ACUTE LUNG INJURY
Citation:
Singh, P., P. S. Gilmour, E H. Boykin, AND M I. Gilmour. ROLE OF CELL SIGNALING IN PROTECTION FROM DIESEL AND LPS INDUCED ACUTE LUNG INJURY. Presented at American Thoracic Society, Orlando, FL, May 21-26, 2004.
Description:
We have previously demonstrated in CD-1 mice that pre-administration of N-acetyl cysteine (NAC) or the p38 MAP kinase inhibitor (SB203580) reduces acute lung injury and inflammation following pulmonary exposures to diesel exhaust particles (DEP) or lipopolysaccharide (LPS). Here we consider that the variable protective capacities of NAC and SB203580 as well as the relative potencies of the two DEP samples and LPS may be related to differences in cellular signaling pathways stimulated by these agents. CD-1 mice were instilled with either 100 g of automobile-generated DEP (A-DEP) rich in organic carbon or off-road source DEP (NIST 2975) rich in elemental carbon, 10 g of LPS, or saline alone 45 min after treatment (po) with either NAC (500 mg/kg) or SB203580 (12.5 mg/kg). Levels of key signaling proteins in lung homogenates were then assayed by western blot. A-DEP and LPS increased phosphospecific p38 MAPk expression compared to NIST 2975 and saline; however, pretreatment with SB203580 increased or potentiated p38 expression in LPS and NIST 2975 exposed lungs, respectively. Pretreatment with NAC potentiated phosphospecific p38 MAPk levels regardless of exposure, yet the greatest effect occurred in NIST 2975 exposed lungs. Toll-like receptor (TLR)-4 was detected in all lung homogenates with somewhat higher levels present in NIST 2975 exposed groups. NAC potentiated TLR-4 expression in LPS treated lungs, while both NAC and SB203580 potentiated its expression in A-DEP exposed groups. Further investigation in a murine alveolar macrophage cell line (MH-S) indicated that both DEP samples were more potent than LPS at inducing TLR-4 and NF-kB and that DEP with higher levels of inorganic carbon have a greater capacity to induce expression of TLR-4 in these cells. We conclude that the protective effects of NAC and SB203580 in the lung may be due in part to potentiation of these cellular signaling pathways. (This abstract does not reflect EPA policy.)