RESUMO
Large difficult to heal ulcers of various etiologies carry a high morbidity and mortality rate. Becaplermin is a recombinant platelet-derived growth factor approved for treatment of diabetic ulcers. In this two-case series, we report the use of becaplermin in the treatment of ulcers due to (i) calciphylaxis, an often fatal condition resulting from systemic calcification and thrombosis of vessels and (ii) pyoderma gangrenosum (PG), a neutrophilic dermatosis. We also report that topical collagenase worsened PG ulcers, consistent with pathergy. Becaplermin can be used to help treat ulcers resulting from calciphylaxis and PG. These encouraging results lend support for the utilization of becaplermin in the treatment of nondiabetic chronic ulcers of various etiologies.
Assuntos
Indutores da Angiogênese/uso terapêutico , Calciofilaxia/tratamento farmacológico , Proteínas Proto-Oncogênicas c-sis/uso terapêutico , Pioderma Gangrenoso/tratamento farmacológico , Adulto , Idoso , Becaplermina , Calciofilaxia/patologia , Humanos , Masculino , Pioderma Gangrenoso/patologia , Úlcera Cutânea/tratamento farmacológico , Úlcera Cutânea/patologia , Resultado do TratamentoRESUMO
The human-infective parasite Trichomonas vaginalis causes the most prevalent nonviral sexually transmitted infection worldwide. Infections in men may result in colonization of the prostate and are correlated with increased risk of aggressive prostate cancer. We have found that T. vaginalis secretes a protein, T. vaginalis macrophage migration inhibitory factor (TvMIF), that is 47% similar to human macrophage migration inhibitory factor (HuMIF), a proinflammatory cytokine. Because HuMIF is reported to be elevated in prostate cancer and inflammation plays an important role in the initiation and progression of cancers, we have explored a role for TvMIF in prostate cancer. Here, we show that TvMIF has tautomerase activity, inhibits macrophage migration, and is proinflammatory. We also demonstrate that TvMIF binds the human CD74 MIF receptor with high affinity, comparable to that of HuMIF, which triggers activation of ERK, Akt, and Bcl-2-associated death promoter phosphorylation at a physiologically relevant concentration (1 ng/mL, 80 pM). TvMIF increases the in vitro growth and invasion through Matrigel of benign and prostate cancer cells. Sera from patients infected with T. vaginalis are reactive to TvMIF, especially in males. The presence of anti-TvMIF antibodies indicates that TvMIF is released by the parasite and elicits host immune responses during infection. Together, these data indicate that chronic T. vaginalis infections may result in TvMIF-driven inflammation and cell proliferation, thus triggering pathways that contribute to the promotion and progression of prostate cancer.
Assuntos
Macrófagos/imunologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/parasitologia , Proteínas de Protozoários/imunologia , Tricomoníase/imunologia , Trichomonas vaginalis/imunologia , Sequência de Aminoácidos , Linhagem Celular Tumoral , Células Cultivadas , Sequência Conservada , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/imunologia , Macrófagos/citologia , Macrófagos/parasitologia , Masculino , Dados de Sequência Molecular , Próstata/imunologia , Próstata/parasitologia , Próstata/patologia , Neoplasias da Próstata/patologia , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Homologia de Sequência , Tricomoníase/complicações , Tricomoníase/parasitologia , Trichomonas vaginalis/genética , Trichomonas vaginalis/metabolismoRESUMO
Trichomonas vaginalis is a common sexually transmitted parasite that colonizes the human urogential tract where it remains extracellular and adheres to epithelial cells. Infections range from asymptomatic to highly inflammatory, depending on the host and the parasite strain. Here, we use a combination of methodologies including cell fractionation, immunofluorescence and electron microscopy, RNA, proteomic and cytokine analyses and cell adherence assays to examine pathogenic properties of T. vaginalis. We have found that T.vaginalis produces and secretes microvesicles with physical and biochemical properties similar to mammalian exosomes. The parasite-derived exosomes are characterized by the presence of RNA and core, conserved exosomal proteins as well as parasite-specific proteins. We demonstrate that T. vaginalis exosomes fuse with and deliver their contents to host cells and modulate host cell immune responses. Moreover, exosomes from highly adherent parasite strains increase the adherence of poorly adherent parasites to vaginal and prostate epithelial cells. In contrast, exosomes from poorly adherent strains had no measurable effect on parasite adherence. Exosomes from parasite strains that preferentially bind prostate cells increased binding of parasites to these cells relative to vaginal cells. In addition to establishing that parasite exosomes act to modulate hostâ¶parasite interactions, these studies are the first to reveal a potential role for exosomes in promoting parasiteâ¶parasite communication and host cell colonization.