Role of gelatinases, their inhbitors, and matrix molecules in cutaneous lesions from american cutaneous leishmaniasis
Leishmaniasis is an important antropozoonosis that affect the entire world. In Brazil, the main clinical form is American cutaneous leishmaniasis (ACL) caused by Leishmania (V.) braziliensis in the most of the cases. This disease is characterized by the formation of wounds at the site of the sand fly bite. The primary lesions are cutaneous, and after their healing or during their evolution, secondary lesions located at mucous tissues can appear as a result of the parasite metastatization. In general, these lesions are predisposed to be chronic, originating ulcers with an intense process of tissue destruction. Throughout the regenerative process, the synthesis and breaking of many different matrix compounds are necessary in order to allow proliferative and migratory events, which will conclude the repairing step. A family of endopeptidases known as matrix metalloproteinases (MMPs) takes part of this process. An important subfamily is the gelatinases MMPs 2 and 9, which are involved in the wound re-epithelization and resolution. MMP activity is strongly controlled by proteins called tissue inhibitors of matrix metalloproteinases (TIMPs). The loss of this control can result in critical tissue degradation. The present work aimed to evaluate the role of gelatinases A (MMP-2) and B (MMP-9), their respective inhibitors TIMPs 2 and 1, and matrix molecules which are substrates for these enzymes in cutaneous ulcers from ACL patients. To achieve this objective, it was used the following techniques: RT-PCR to evaluate the gelatinases and TIMPs mRNA expression, in situ zymography to visualize the tissue sites of gelatinases activity, and immunohistochemistry to detect fibronectin, type IV collagen, laminin, and tenascin. At last, data were correlated to important clinical variables of ACL. It was found that patients that have a low frequency of MMPs and TIMPs mRNA expression also showed a bad responsiveness to therapy, lesions greater than 5.8 cm2, and/or lesion located at the lower limbs, in addition to an intense gelatinase activity and a high matrix molecules expression. These facts suggest that the imbalance between MMPs synthesis and activity can impair the healing process. Moreover, recent lesions express high levels of gelatinases, while the old ones seem to have high expression levels of inhibitors, what can favor the healing process. Therefore, we suggest that gelatinases and their inhibitors can be important in the leishmanial lesions outcome.
School:Faculdades Oswaldo Cruz
Source Type:Master's Thesis
Keywords:leishmaniose braziliensis gelatinases cutaneous leishmaniasis cellular matrix
Date of Publication:04/03/2006