The role of active inducible nitric oxide synthase expression in the pathogenesis of capillary leak syndrome resulting from interleukin-2 therapy in mice.

Previously, we showed that nitric oxide (NO) plays a major role in the pathogenesis of IL-2-induced capillary leak syndrome in healthy or mammary adenocarcinoma-bearing C3H/HeJ mice. NO synthase (NOS) inhibitors, such as NG-nitro-L-arginine methyl ester (L-NAME) reduced all the manifestations of IL-2-induced capillary leakage, without compromising the antitumor effects of IL-2. The present study was carried out on healthy C3H/HeJ mice subjected to one or two 4-day rounds of systemic IL-2 therapy with or without oral L-NAME therapy to: (a) identify the tissue source of NOS activity and NOS protein induced by IL-2 therapy; (b) identify histologically the nature of the structural damage to the lungs associated with IL-2 therapy-induced pulmonary edema; and (c) evaluate the effects of additional L-NAME therapy on the above-mentioned parameters. Results revealed that IL-2 therapy in healthy mice resulted in the expression of inducible NOS in numerous tissues including the endothelium and muscles of the anterior thoracic wall as well as splenic macrophages. One round of IL-2 therapy resulted in high levels of inducible NOS (iNOS) activity in the anterior thoracic wall accompanied by pleural effusion. After two rounds of IL-2 therapy, there was neither pleural effusion nor high iNOS activity in the thoracic wall. IL-2-induced pulmonary edema after one round of therapy correlated to both a significant rise in NO production measured in the serum and structural damage to the lungs and its capillaries. Addition of the NOS inhibitor L-NAME totally eradicated NOS activity but not necessarily iNOS expression. It also reduced IL-2-induced pulmonary edema and pleural effusion, restrained the rise in the levels of NO metabolites (nitrites and nitrates) in the serum and pleural effusion, and significantly restored the structural integrity of the lungs after one round of therapy. Thus, NOS inhibitors may be beneficial adjuncts to IL-2 therapy for cancer and infectious diseases.