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.