Modification of HIF-1α, NF-κB, IGFBP-3, VEGF and adiponectin in diabetic foot ulcers treated with hyperbaric oxygen
Authors:   División de Laboratorios de Vigilancia e Investigación Epidemiológica, Coordinación de Vigilancia Epidemiológica, Instituto Mexicano del Seguro Social, CDMX 03100, México, Anguiano-Hernandez Yu Mei ,   Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, CDMX México, Contreras-Mendez Lilia ,   División de Laboratorios de Vigilancia e Investigación Epidemiológica, Coordinación de Vigilancia Epidemiológica, Instituto Mexicano del Seguro Social, CDMX 03100, México,   Posgrado en Ciencias Biológicas, UNAM, CDMX México, Hernandez-Cueto Maria de los Angeles ,   División de Laboratorios de Vigilancia e Investigación Epidemiológica, Coordinación de Vigilancia Epidemiológica, Instituto Mexicano del Seguro Social, CDMX 03100, México, Alvarado-Yaah Julio Elias ,   División de Laboratorios de Vigilancia e Investigación Epidemiológica, Coordinación de Vigilancia Epidemiológica, Instituto Mexicano del Seguro Social, CDMX 03100, México, Muñoz-Medina Jose Esteban ,   División de Laboratorios de Vigilancia e Investigación Epidemiológica, Coordinación de Vigilancia Epidemiológica, Instituto Mexicano del Seguro Social, CDMX 03100, México, Santillan-Verde Marco Antonio ,   Posgrado en Ciencias Biológicas, UNAM, CDMX México, Barbosa-Cabrera Reyna Elizabeth ,   Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, CDMX México, Delgado-Quintana rlos Alberto ,   Servicio de Oxigenoterapia, Hospital de Infectología, IMSS, CDMX México, Trejo-Rosas Saul ,   Servicio de Oxigenoterapia, Hospital de Infectología, IMSS, CDMX México, Santacruz-Tinoc Clara Esperanza o ,   División de Laboratorios de Vigilancia e Investigación Epidemiológica, Coordinación de Vigilancia Epidemiológica, Instituto Mexicano del Seguro Social, CDMX 03100, México, Gonzalez-Ibarra Joaquin ,   División de Laboratorios de Vigilancia e Investigación Epidemiológica, Coordinación de Vigilancia Epidemiológica, Instituto Mexicano del Seguro Social, CDMX 03100, México, Gonzalez-Bonilla Cesar R. ,   División de Laboratorios de Vigilancia e Investigación Epidemiológica, Coordinación de Vigilancia Epidemiológica, Instituto Mexicano del Seguro Social, CDMX 03100, México
Published: December 2020

Introduction: Diabetic foot ulcers are a frequent complication of diabetes and the first cause of non-traumatic lower limb amputation. They affect quality of life, restrict social productivity and generate a high economic burden for health care systems. Hyperbaric oxygen (HBO2) therapy is an adjunctive treatment option because it improves wound healing in the short term. However, its ability to modulate the pro- and anti-inflammatory balance and the hypoxic cell response in the clinical setting has not been fully described. Objective: To determine modifications in HIF-1α, NF-κB, IGFBP-3, and VEGF expression in wounds as well as circulating inflammatory cytokines in patients with diabetic foot ulcers subjected to HBO2. Materials and methods: We studied 17 ambulatory patients and one hospitalized patient with diabetic foot ulcers classified as Grade 3 or 4 according to the Wagner scale. All underwent HBO2 therapy. Tissue expression of HIF-1α, NF-κB, IGFBP-3 and VEGF was determined by immunohistochemistry. Plasma levels of adiponectin, IL-6, IFN-γ, IL-10 and IL-4 were measured by ELISA and chemiluminescence. Fibrosis and angiogenesis were determined by Masson’s trichrome staining. Results: Ulcers in all patients healed after one month of HBO2, and none presented relapses at the one-year follow-up. At the beginning of treatment, HIF-1α and NF-κB expression was observed mainly in the nucleus, whereas these proteins were localized in the cytoplasm at the end of HBO2. There were significant modifications in VEGF expression after therapy, an increase in the plasma level of proinflammatory IL-6, and a decrease in that of IFN-γ. IGFBP-3 expression and plasma levels of adiponectin were increased at the end of HBO2. Increases in fibrosis and angiogenesis were also observed. Conclusions: These results suggest that adjuvant HBO2 modifies the proinflammatory balance related to the cellular response to hypoxia.