Candida albicans-induced activation of the TGF-β/Smad pathway and upregulation of IL-6 may contribute to intrauterine adhesion

Abstract

Iatrogenic injury to endometrial tissue is the main cause of intrauterine adhesions (IUA) and infection can also damage the endometrium. The microbiota plays an important role in the health of the female reproductive tract. However, the mechanism is still unclear. In total, 908 patients with IUA and 11,389 healthy individuals were retrospectively selected for this clinical study. Participant information including vaginal microecological results and human papillomavirus (HPV) status were collected. Univariate and multivariate logistic regression analyses were used to identify the factors related to IUA. Next, animal experiments were performed in a curettage-induced IUA rat model. After the procedure, rats in the experimental group received a vaginal infusion of a Candida albicans (C. albicans) fungal solution. On days 3, 7, and 14 after curettage and infusion, the expression levels of IL-6, fibrotic pathway-related factors (TGF-β1, Smad 2, and COL1), and estrogen receptor (ER) and progesterone receptor (PR) in rat endometrial tissues were assessed. Fungal infection of the reproductive tract was found to be an independent risk factor for IUA (P < 0.05). The inflammatory response and degree of fibrosis were greater in rats infected with C. albicans than in the controls. The levels of IL-6, TGF-β1, Smad 2, and COL1 expression in endometrial tissues were significantly higher in the experimental group than in the control group (P < 0.05). However, the ER and PR levels were lower in the IUA group than in the non-IUA group (P < 0.05). C. albicans infection may be related to IUA. C. albicans elicits a strong inflammatory response that can lead to more severe endometrial fibrosis.

Figure 1

General appearance of uterine specimens on day 3 after Candida albicans (CA) injection into the reproductive tract of rats (right) compared with the control group (left). CA, Candida albicans group.

Figure 2

H&E staining of rat endometrial tissues on postoperative days 3, 7, and 14 in the Candida albicans and control groups. (A) On day 3, H&E staining results in the control group show suppurative necrosis (black arrows) and local edema (green arrow). (B,C) H&E staining results in the control group on the day 7 and 14. (D) On day 3, H&E staining results in the C. albicans group show neutrophils (black arrow) and lamina propria edema (green arrows). (E) On day 7, H&E staining results in the C. albicans group show local uterine epithelial cytoplasmic vacuolation (blue arrow), a small number of lymphocytes (yellow arrow), and more collagen fiber hyperplasia (green arrow) in the lamina propria. (F) On day 14, H&E staining results in the C. albicans group show inflammatory exfoliation and deletion of the uterine epithelium (black arrow). H&E hematoxylin and eosin.

Figure 3

Masson’s trichrome staining of rat endometrial tissues in the control and C. albicans groups on postoperative days 3, 7, and 14. (A,B) Masson trichrome staining results in the control group on the day 3 and 7. (C) On day 14, staining results in the control group show slight, collagen fiber proliferation (black arrow). (D) On day 3, staining results in the C. albicans group show severe collagen fiber hyperplasia (black arrow). (E) On day 7, staining results in the C. albicans group show extremely severe hyperplasia of the collagen fibers, with some of the fibers forming strips (black arrow). (F) On day 14, staining results in the C. albicans group show severe collagen fiber proliferation can be seen, with some of the fibers forming strips.

Figure 4

Immunohistochemical staining of IL-6, TGF-β1, Smad 2, COL1, ER, and PR in the C. albicans and control groups (×400). IL-6 interleukin-6, TGF-β1 transforming growth factor-β1, ER estrogen receptor, PR progesterone receptor.