TREATMENT OF PARACOCCIDIOIDES-BRASILIENSIS-INFECTED MICE WITH A NITRIC-OXIDE INHIBITOR PREVENTS THE FAILURE OF CELL-MEDIATED IMMUNE-RESPONSE

The activation of the nitric oxide (NO) production system and its invo lvement in the control of the lung fungal burden and in immunosuppress ion mechanisms were studied during the course of Paracoccidioides bras iliensis-infected mice. Mice that had been infected with the fungus we re treated daily with a specific inhibitor of NO synthesis, N omega-ni tro-L-arginine, or with buffered saline (control); NO production was a ssessed on the basis of spontaneous NO, production by bronchoalveolar and peritoneal macrophages (M phi) and of serum NO; levels. The infect ion coursed with an elevation of NO, levels. The M phi produced NO; an d released TNF-alpha only after stimulation with LPS, In addition, the immunoproliferative responses of spleen cells that had been stimulate d with the fungus Ag or with Con A were depressed. An examination of t he lungs of infected animals showed a progressive increase in the size of the lesions. Treatment of the animals, which resulted in an inhibi tion of NO2- production by M phi and a reduction of serum NO3- levels, caused the spontaneous release of TNF-alpha from infected animals and prevented the failure of the lymphoproliferative capacity of spleen c ells. Furthermore, the treatment resulted in less pulmonary damage des pite the fact that the lung fungal burden increased. It was also demon strated that the NO donors S-nitroso-acetyl penicillamine and 3-morpho lino-sydnonimine-hydrochloride were able to inhibit the growth of P. b rasiliensis in vitro. These results suggest that although NO is import ant for the killing of the fungi, the activation of NO production in P , brasiliensis infection contributes to the occurrence of the immunosu ppression observed during the course of the infection.