Abstract
BackgroundAlthough the testis is considered an immunoprivileged organ it can orchestrate immune responses against pathological insults such as infection and trauma. Experimental autoimmune orchitis (EAO) is a model of chronic inflammation whose main histopathological features it shares with human orchitis. In EAO an increased number of macrophages infiltrate the interstitium concomitantly with progressive germ cell degeneration and impaired steroidogenesis. Up-regulation of nitric oxide (NO)-NO synthase (NOS) system occurs, macrophages being the main producers of NO.ObjectiveThe aim of our study was to evaluate the role of NO-NOS system in orchitis development and determine the involvement of NO released by testicular macrophages on germ cell apoptosis and testosterone secretion.Method and ResultsEAO was induced in rats by immunization with testicular homogenate and adjuvants (E group) and a group of untreated normal rats (N) was also studied. Blockage of NOS by i.p. injection of E rats with a competitive inhibitor of NOS, L-NAME (8mg/kg), significantly reduced the incidence and severity of orchitis and lowered testicular nitrite content. L-NAME reduced germ cell apoptosis and restored intratesticular testosterone levels, without variations in serum LH. Co-culture of N testicular fragments with testicular macrophages obtained from EAO rats significantly increased germ cell apoptosis and testosterone secretion, whereas addition of L-NAME lowered both effects and reduced nitrite content. Incubation of testicular fragments from N rats with a NO donor DETA-NOnoate (DETA-NO) induced germ cell apoptosis through external and internal apoptotic pathways, an effect prevented by N-acetyl-L-cysteine (NAC). DETA-NO inhibited testosterone released from Leydig cells, whereas NAC (from 2.5 to 15 mM) did not prevent this effect.ConclusionsWe demonstrated that NO-NOS system is involved in the impairment of testicular function in orchitis. NO secreted mainly by testicular macrophages could promote oxidative stress inducing ST damage and interfering in Leydig cell function.
Highlights
Male genital tract inflammation, mainly orchitis and orchi-epididymitis, are relevant co-factors of human subfertility and infertility
Co-culture of N testicular fragments with testicular macrophages obtained from Experimental autoimmune orchitis (EAO) rats significantly increased germ cell apoptosis and testosterone secretion, whereas addition of L-NAME lowered both effects and reduced nitrite content
We demonstrated that nitric oxide (NO)-NO synthase (NOS) system is involved in the impairment of testicular function in orchitis
Summary
Mainly orchitis and orchi-epididymitis, are relevant co-factors of human subfertility and infertility. Infiltrating immune cells can produce a pro-inflammatory microenvironment that might be responsible for impairment of spermatogenesis in orchitis. Infiltrating immune cells synthesize pro-inflammatory cytokines Th1 (IL-6, TNF-α IFN-γ) and Th17 (IL-17, IL-21 and IL-23) and produce pro-oxidative species formed from oxygen and/or nitrogen like hydrogen peroxide and nitric oxide (NO). Increased expression of NO synthase (NOS) has been described in the testis of infertile patients and oxidative stress proposed as a detrimental condition for male reproductive health [3,4,5]. In EAO an increased number of macrophages infiltrate the interstitium concomitantly with progressive germ cell degeneration and impaired steroidogenesis. Up-regulation of nitric oxide (NO)-NO synthase (NOS) system occurs, macrophages being the main producers of NO
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