Diesel exhaust particles (DEP) are known to suppress the innate immune responses of alveolar macrophages (AM) against bacterial infection. In particular, although DEP induce AM production of nitric oxide (NO) through particle stimulation, the organic component of DEP strongly inhibits pathogen-induced NO production by AM. The present study examined whether NO may affect the secretion of pro- and anti-inflammatory cytokines by AM resulting in suppression of the host defense in response to DEP exposure. Male Sprague-Dawley rats were intratracheally (IT) in-stilled with saline or DEP (35 mg/kg body weight). To inhibit DEP-induced inducible nitric oxide synthase (iNOS), another group of rats were treated with an iNOS inhibitor, aminoguanidine (AG), by i.p. injection of 100 mg/kg AG, 30 min prior to and 3, 6 and 9 h after IT instillation of DEP or saline. Rats were sacrificed at 1 day post-DEP exposure, and AM were harvested. The results show that DEP induced iNOS expression in AM, which was not affected by AG. AG did not affect DEP-induced inflammatory markers in the lung (neutrophil infiltration and protein content), but significantly lowered the DEP-induced iNOS activity in AM. The production of nitrite by DEP-exposed AM was reduced from 52 +/- 16 to 18 +/- 4 uM by AG treatment. AG treatment inhibited the secretion of TNF- , pro- inflammatory cytokine, by AM in response to DEP exposure (from 3424 +/- 676 to 1511 +/- 428 pg/ml). DEP exposure induced AM production of IL-10, an anti-inflammatory cytokine that is often induced by intracellular pathogens to dampen the host defense mechanism. Inhibition of iNOS activity by AG further enhanced this DEP-induced IL-10 production (from 38 +/- 20 to 199 +/- 86 pg/ml), suggesting that NO, by inhibiting IL-10, plays an important anti-bacterial role. In summary, this study shows that inhibition of NO by AG significantly decreases TNF- secretion, while further enhancing IL-10 production by DEP-exposed AM. This change in pro-/anti-inflammatory cytokine balance may make the lung more susceptible to bacterial infection.
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland