title: Therapeutic failure in American cutaneous leishmaniasis is associated with gelatinase activity and cytokine expression.
abstract: Cutaneous lesions caused by Leishmania braziliensis infection occasionally heal spontaneously, but with antimonials therapy heal rapidly in approximately 3 weeks. However, about 15% of the cases require several courses of therapy. Matrix metalloproteinase-2 (MMP-2) and MMP-9 are gelatinases that have been implicated in other chronic cutaneous diseases and skin re-epithelialization. These enzymes are controlled by their natural inhibitors [tissue inhibitors of metalloproteinase (TIMPs)] and by some cytokines. Uncontrolled gelatinase activity may result in intense tissue degradation and, consequently, poorly healing wounds. The present study correlates gelatinase activity to therapeutic failure of cutaneous leishmaniasis (CL) lesions. Our results demonstrate an association between gelatinase activity and increased numbers of cells making interferon (IFN)-γ, interleukin (IL)-10 and transforming growth factor (TGF)-β in lesions from poor responders. Conversely, high levels of MMP-2 mRNA and enhanced MMP-2 : TIMP-2 ratios were associated with a satisfactory response to antimonials treatment. Additionally, high gelatinolytic activity was found in the wound beds, necrotic areas in the dermis and within some granulomatous infiltrates. These results indicate the importance of gelatinase activity in the skin lesions caused by CL. Thus, we hypothesize that the immune response profile may be responsible for the gelatinase activity pattern and may ultimately influence the persistence or cure of CL lesions.
authors.affiliation: Instituto Oswaldo Cruz at FIOCRUZ, Rio de Janeiro, RJ, Brazil. anamaretti@ioc.fiocruz.br
authors.forename: A C
authors.initials: AC
authors.lastname: Maretti-Mira
authors.forename: M P
authors.initials: MP
authors.lastname: de Oliveira-Neto
authors.forename: A M
authors.initials: AM
authors.lastname: Da-Cruz
authors.forename: M P
authors.initials: MP
authors.lastname: de Oliveira
authors.forename: N
authors.initials: N
authors.lastname: Craft
authors.forename: C
authors.initials: C
authors.lastname: Pirmez
mesh_terms: D000328:Adult; D000965:Antimony / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008536:Meglumine / Q000627:therapeutic use*; D000077485:Meglumine Antimoniate; D009942:Organometallic Compounds / Q000627:therapeutic use*; D012038:Regeneration; D012867:Skin / Q000201:enzymology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000276:immunology; D017211:Treatment Failure
chemical_list: D000981:Antiprotozoal Agents; D016207:Cytokines; D009942:Organometallic Compounds; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D008536:Meglumine; D000077485:Meglumine Antimoniate; D007371:Interferon-gamma; D000965:Antimony; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9