Involvement of cystic fibrosis transmembrane conductance regulator (CFTR) in the pathogenesis of hydrosalpinx induced by Chlamydia trachomatis infection.

BACKGROUND: Genital Chlamydia (C) trachomatis infection has been recognized as the single most common cause of pelvic inflammatory disease leading to severe tubal damage, ectopic pregnancy, infertility and hydrosalpinx. However, the mechanism underlying the formation of hydrosalpinx induced by C. trachomatis infection remains largely unknown. We performed this study to determine the involvement of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel that regulates epithelial electrolyte and fluid secretion, in hydrosalpinx fluid formation. METHODS: Western blot analysis was used to determine CFTR expression in the hydrosalpinges that were seen on the ultrasound scans of infertile assisted reproduction treatment patients. Correlation with C. trachomatis infection was done by testing patients' sera for C. trachomatis immunoglobulin G antibody titer using a Capita enzyme-linked immunosorbent assay based kit. CFTR involvement was further verified in a rat C. trachomatis infection model and confirmed using CFTR mutant (CFTR(tm1Unc)) mice. RESULTS: Here we report on the up-regulated expression of CFTR in the hydrosalpinx tissues of infertile patients with detectable serum levels of C. trachomatis antibody (immunoglobulin G). In a rat model, increased CFTR expression and fluid accumulation could be observed in the uterine horns infected with C. trachomatis elementary bodies, which was reversed by antibiotics treatment. In C. trachomatis-infected CFTR(tm1Unc) mice, however, no detectable fluid accumulation was observed. CONCLUSION: These findings suggest the involvement of CFTR in the pathogenesis of hydrosalpinx fluid formation and may provide grounds for a better treatment strategy to improve assisted reproduction treatment outcome in infertile patients with hydrosalpinx.

Involvement of cystic fibrosis transmembrane conductance regulator in infection-induced edema.

Abnormal fluid accumulation in tissues, including the life-threatening cerebral and pulmonary edema, is a severe consequence of bacteria infection. Chlamydia (C.) trachomatis is an obligate intracellular gram-negative human pathogen responsible for a spectrum of diseases, causing tissue fluid accumulation and edema in various organs. However, the underlying mechanism for tissue fluid secretion induced by C. trachomatis and most of other infectious pathogens is not known. Here, we report that in mice C. trachomatis infection models, the expression of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP activated chloride channel, is up regulated together with increased cytokine release and tissue fluid accumulation that can be reversed by treatment with antibiotic specific for C. trachomatis and CFTR channel blocker. However, C. trachomatis infection cannot induce tissue edema in CFTRtm1Unc mutant mice. Administration of exogenous IL-1beta to mice mimics the C. trachomatis infection-induced CFTR upregulation, enhanced CFTR channel activity and fluid accumulation, further confirming the involvement of CFTR in infection-induced tissue fluid secretion.

Estrogen-induced abnormally high cystic fibrosis transmembrane conductance regulator expression results in ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) remains one of the most life-threatening and potentially fatal complications of assisted reproduction treatments, arising from excessive stimulation of the ovaries by exogenous gonadotropins administrated during in vitro fertilization procedures, which is characterized by massive fluid shift and accumulation in the peritoneal cavity and other organs, including the lungs and the reproductive tract. The pathogenesis of OHSS remains obscure, and no definitive treatments are currently available. Using RT-PCR, Western blot, and electrophysiological techniques we show that cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel expressed in many epithelia, is involved in the pathogenesis of OHSS. Upon ovarian hyperstimulation, rats develop OHSS symptoms, with up-regulated CFTR expression and enhanced CFTR channel activity, which can also be mimicked by administration of estrogen, but not progesterone, alone in ovariectomized rats. Administration of progesterone that suppresses CFTR expression or antiserum against CFTR to OHSS animals results in alleviation of the symptoms. Furthermore, ovarian hyperstimulation does not induce detectable OHSS symptoms in CFTR mutant mice. These findings confirm a critical role of CFTR in the pathogenesis of OHSS and may provide grounds for better assisted reproduction treatment strategy to reduce the risk of OHSS and improve in vitro fertilization outcome.

Plasticity of rat bone marrow-derived 5-hydroxytryptamine-sensitive neurons: dedifferentiation and redifferentiation.

Inducing cellular dedifferentiation has been proposed as a potential method for enhancing endogenous regeneration in mammals. Here we demonstrate that phenotypic and functional neurons derived from adult rat bone marrow stromal stem cells (MSCs) can be induced to undergo dedifferentiation, then proliferation and redifferentiation. In addition to morphological changes and expression of neuronal markers, neuron-specific enolase and neurofilament H, functional differentiation was monitored by intracellular Ca2+ mobilization in response to a ubiquitous neurotransmitter, 5-hydroxytryptamine (5-HT) at different stages. The neurons derived from rMSCs were found to have increased 5-HT response. This 5-HT sensitivity could be reversed to basal level similar to that found in rMSCs when neurons, up to 3 days after neuronal induction, were induced to undergo dedifferentiation. Increase in 5-HT-induced Ca2+ mobilization was again observed when rMSCs derived from dedifferentiated neurons were induced to redifferentiate into neurons again. Variation in 5-HT1A receptor immunoreactivity was observed in stem cells, differentiated neurons, dedifferentiated neurons and redifferentiation neurons, consistent with their respective 5-HT sensitivity. These results suggest that adult bone marrow-derived 5-HT sensitive neurons are capable of dedifferentiation, then proliferation and redifferentiation, indicating their plasticity and potential use in treatment of neural degenerative diseases.