Conjunctival Expression of Matrix Metalloproteinase and Proinflammatory Cytokine Genes after Trichiasis Surgery

Abstract

PURPOSE. Trachoma, the leading infectious cause of blindness, is a chronic inflammatory scarring condition. Blindness follows the development of trichiasis, which is treated surgically. Unfortunately, it frequently recurs, compromising the treatment. In this study, gene expression analysis was used to examine factors that may be involved in the inflammation and tissue remodeling after surgery. METHODS. Subjects were examined before and at 1 and 4 years after surgery. Conjunctival swab samples were collected for bacterial culture, Chlamydia trachomatis PCR, and RNA isolation at 1 year. Quantitative real-time PCR was performed to measure the expression of tumor necrosis factor-alpha (TNF), interleukin-1beta (IL1B), matrix metalloproteinase-1 (MMP1), MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), TIMP-2, and hypoxanthine phosphoribosyl transferase-1 (HPRT1). RESULTS. Two hundred forty individuals with trachomatous trichiasis were recruited. One year after surgery, recurrent trichiasis was associated with a reduced MMP-1/TIMP-1 ratio (P = 0.029). IL1B expression was elevated in the presence of either conjunctival bacterial infection (P = 0.011) or inflammation (P = 0.002). TNF expression was greater in the Mandinka ethnic group (P < 0.0001), and it was increased when clinical inflammation was associated with nonchlamydial bacterial infection (P = 0.012). MMP-9 expression increased when conjunctival inflammation was associated with bacterial infection (P = 0.007). CONCLUSIONS. Recurrent trichiasis was associated with a reduced MMP-1 to TIMP-1 ratio, which may favor the accumulation of fibrotic tissue. Nonchlamydial bacterial infection may induce factors that contribute to conjunctival tissue remodeling and recurrent trichiasis in trachoma. Prospective studies are needed to assess the potential importance of these and other factors in progressive disease.

Innate Immune Responses and Modified Extracellular Matrix Regulation Characterize Bacterial Infection and Cellular/Connective Tissue Changes in Scarring Trachoma

“…Matrix metalloproteinases are capable of degrading the protein components of the ECM and also have wide-ranging effects on inflammatory and immune responses (50,58). Previous studies have implicated MMPs in the pathogenesis of trachomatous scarring, and this was further confirmed in the present study in a separate population (9,10,14,20,29,44). MMP7, MMP9, MMP12, and TIMP1 were upregulated in scarring and inflammation, whereas MMP10 and SPARCL1 were downregulated.…”

“…Infection with other bacteria was more frequent, and many of the genes described above involved in innate immunity showed moderate to large increases in expression if a pathogenic organism was present. A previous study found that the presence of bacterial infection was associated with increased expression of IL1B, TNF-␣, MMP1, MMP9, and TIMP2 after trichiasis surgery (10). In the present study, bacterial infection was also found to be associated with an increased inflammatory infiltrate and tissue edema with IVCM.…”

Conjunctival Transcriptome in Scarring Trachoma

“…It is also likely that nonchlamydial bacterial infections stimulate the inflammatory response, especially where there is established tissue disruption caused by repeated C. trachomatis infection. (10) In addition to the epithelium, other cells, such as macrophages and neutrophils, probably contribute to the production of these proinflammatory mediators.…”

“…Studies of C. trachomatis infection in a monkey model demonstrated that after a primary infection the inflammatory phenotype could be induced by inoculating the conjunctiva with the C. trachomatis HSP60 antigen (66). There are some data on the immunological response in early active trachoma; however, there is limited information about the cicatricial stage (10,28,30,44,45). It is unknown which fibrogenic pathways are important to this disease process and what drives them.…”

“…In addition, there is mounting evidence for the importance of T H 2 responses in other infectious diseases that produce scarring such as schistosomiasis, which may be mediated by interleukin-13 (IL-13) and alternative macrophage activation (73). There are also some data indicating that factors such as the matrix metalloproteinases may be involved in the tissue remodeling process in trachoma (9,10,21,30).…”