Berlanga-Acosta J, Vázquez-Blomquist D, Cibrián D, Mendoza Y, Ochagavía ME, Miranda J, Suárez J, González-Ferrer Y, Vila JM, Abreu A, Ugarte-Moreno D, Cruz Y, Howland I, Coro-Antich R, León OS, Bringas R, García-del Barco D, Cosme-Díaz K, Palenzuela D, Fernández JR, Nazabal M, Guillén I, Cintado A, Inés L, López-Mola E, Guillén-Nieto GE

Language: English
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Page: 60-72
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ABSTRACT

Tissue fibrosis is a leading cause of morbidity and mortality. Current treatments for conditions such as hepatic fibrosis have been unsuccessful. The growth hormone relasing peptide 6 (GHRP6) is endowed with cardioprotective actions but its antifibrotic effect had not been anticipated. We examined the GHRP6 ability to prevent and revert liver cirrhosis after induction in Wistar rats by a subcutaneous administration of CCl4. GHRP6 effects were examined after concomitant and delayed administration to toxic respectively. The percentages of hepatic fat, fibrosis, nodularity and septae thickness were histologically and morphometrically determined. Ascitis and portal dilation were judged by ultrasound and serum biochemical profile and oxidative stress parameters determined. Mechanistic involvement of selective gene/proteins was assessed by RT-PCR and immunohistochemistry. Microarrays showed gene expression profiles of GHRP6-treated liver samples on CapitalBio Rat Genome Oligo Array. GHRP6 concomitant intervention prevented in more than 85% parenchymal fibrotic induration (p < 0.0001) and therapeutic administration for only 15 days allowed for 37% fibrotic clearance (p = 0.0004) with more than 30% reduction of septae thickness (p = 0.0011). The 60 days GHRP6 administration scheme produced a 75% reduction of the fibrotic area with more than 60% reduction of nodularity. GHRP6 reduced oxidative damage enhancing the activity of antioxidant enzymes. Vimentin and alpha smooth muscle actin immunodetection profile indicated GHRP6 reduced the number of activated stellate cells. GHRP6 administration reduced fibrogenic factors as TGF-β and CTGF on Kupffer cells. Differentially expressed genes in the microarray experiment indicated GHRP6 modulate the redox balance and parenchymal cells response to injury. These evidences suggest GHRP6 may control the liver’s fibroplastic response.