Inhibition of Matrix Metalloproteinases Protects Mice from Ascending Infection and Chronic Disease Manifestations Resulting from UrogenitalChlamydia muridarumInfection

Abstract

Matrix metalloproteinases (MMP) are a family of host-derived enzymes involved in the turnover of extracellular matrix molecules. We have previously reported enhanced expression of matrix metalloproteinases in Chlamydia muridarum urogenital tract infection of female mice. Kinetics and patterns of MMP expression as well as enhanced expression in susceptible strains of mice in the prior study implied a role for MMP in pathogenesis. To explore this further, we infected a susceptible strain of mice (C3H/HeN) with C. muridarum and treated two groups of mice with either one of two chemical inhibitors of MMP (MMPi; captopril and a chemically modified tetracycline) and reserved infected sham-treated mice as controls. Neither of the treatments affected shedding of viable chlamydiae from the lower urogenital tract, but the administration of either MMPi protected mice from the formation of hydrosalpinx-a surrogate marker of oviduct occlusion and infertility. Interestingly, the mechanism of protection for mice treated with chemically modified tetracycline 3, appeared to be related to prevention of ascending upper genital tract infection. These results imply that MMP are involved in pathogenesis of chlamydial infection in this model by mediating ascension of the infection into the upper genital tract. The mouse model of female urogenital tract infection withChlamydia muridarum (previously, the mouse pneumonitis strain of Chlamydia trachomatis, MoPn) has been used for over 20 years to study immunological protection related to chlamydial infections (25). More recently, it has been used to study pathological immune responses during chlamydia infection. Hydrosalpinx formation, infertility, and fibrotic oviduct occlusion are routine consequences of infection following a single urogenital inoculation of Chlamydia muridarum in susceptible mouse strains. Each of these manifestations is positively correlated with the others and also occurs in resistant strains, but at a lower rate (8,30).We have found that nitrogen and oxygen radicals interact to have a major role in influencing pathogenesis in this model (23). In the absence of phagocyte oxidase, mice are spared from the chronic sequelae of hydrosalpinx and infertility following chlamydial infection, whereas the loss of inducible nitric oxide synthase significantly increases the rate of chronic sequelae. Interestingly, oxygen and nitrogen radicals have likewise been shown to have regulatory effects on host enzymes that influence the degradation of extracellular matrix (ECM) and fibrosis (13). The matrix metalloproteinases (MMP) are a class of zinc-dependent enzymes that are involved in the proteolysis and resynthesis of the ECM (18, 44), processing of cytokines to active forms (19), release of sequestered growth and signaling factors (14), and chemotaxis and migration of leukocytes through inflamed tissues (17,40,41). In addition to a pivotal role in fibrosis, MMP activity has been linked to atherosclerosis (11), angiogenesis associated with tumor growth and metastasis (5), and rheum...

Caspase-1 Contributes toChlamydia trachomatis-Induced Upper Urogenital Tract Inflammatory Pathologies without Affecting the Course of Infection

“…It has been shown that inhibition of the IL-1␤-inducible MMPs with chemical inhibitors, although failing to alter the course of chlamydial infection, can significantly suppress inflammatory pathologies in mouse oviducts during chlamydial infection (18), which very much mimics the phenotype of caspase-1 deficiency. However, because MMPs can also be induced by pathways independent of caspase-1, it is unlikely that the redundantly regulated MMPs are responsible for the caspase-1-dependent exacerbation of oviduct inflammation.…”

“…Although caspase-1-mediated pathways can lead to the production of many other effector molecules, these effector molecules may not contribute to the host defense against chlamydial infection. For example, IL-6, nitric oxide, and MMPs, which are inducible by the caspase-1-activated IL-1␤, have been shown to play little role in clearing chlamydial infection in the urogenital tract (18,34). Together, the analyses described above suggest that caspase-1-mediated responses are unable to affect chlamydial infection.…”

“…The sections were stained with hematoxylin and eosin (H&E) as described elsewhere (40). The H&E-stained sections were assessed by a certified pathologist (I-T.Y) blinded to mouse treatment, and the severity of inflammation and pathologies was scored based on the modified schemes established previously (18,27,40). The uterine horns and fallopian tubes were scored separately.…”

“…Furthermore, it was found that although the inducible nitric oxide synthase did not prevent chlamydial infection in mice (17,37), it protected mice from the chlamydial infection-induced genital tract pathologies (38). In contrast, host matrix metalloproteinases (MMPs) seem to exacerbate chronic inflammatory pathologies resulting from urogenital C. muridarum infection, although they also do not affect the course of infection (18). It appears that MMP-7 is not required for the MMP-mediated exacerbation of inflammation since mice deficient in MMP-7 did not show any significant reduction in Chlamydia-induced urogenital tract pathologies (31).…”

Mice Deficient in MyD88 Develop a Th2-Dominant Response and Severe Pathology in the Upper Genital Tract following Chlamydia muridarum Infection

“…The H&E-stained sections were assessed by a certified pathologist (I-T.Y.) blinded to mouse treatment and scored for severity of inflammation and pathologies based on the modified schemes established previously (10,42,43). The uterine horns and fallopian tubes were scored separately.…”