The multifaceted role of pirfenidone and its novel targets

<p>Abstract</p> <p>Background</p> <p>Pirfenidone (PFD) is a molecule that exhibits antifibrotic properties in a variety of <it>in vitro </it>and animal models of lung, liver and renal fibrosis. These pathologies share many fibrogenic pathways with an abnormal fibrous wound-healing process; consequently, tissue repair and tissue regeneration-regulating mechanisms are altered.</p> <p>Objective</p> <p>To investigate the usefulness of PFD as an antifibrotic agent in clinical and experimental models of fibrotic disease.</p> <p>Conclusions</p> <p>There is a growing understanding of the molecular effects of PFD on the wound healing mechanism, leading to novel approaches for the management of fibrosis in lung, liver and renal tissues. Although the optimum treatment for fibrosis remains undefined, it is possible that combined therapeutic regimens that include this wide-application molecule, pirfenidone, could offer a useful treatment for fibrotic disease.</p

Combinatorial gene therapy renders increased survival in cirrhotic rats

<p>Abstract</p> <p>Background</p> <p>Liver fibrosis ranks as the second cause of death in México's productive-age population. This pathology is characterized by acummulation of fibrillar proteins in hepatic parenchyma causing synthetic and metabolic disfunction. Remotion of excessive fibrous proteins might result in benefit for subjects increasing survival index. The goal of this work was to find whether the already known therapeutical effect of human urokinase Plasminogen Activator and human Matrix Metalloprotease 8 extends survival index in cirrhotic animals.</p> <p>Methods</p> <p>Wistar rats (80 g) underwent chronic intoxication with CCl₄: mineral oil for 8 weeks. Cirrhotic animals were injected with a combined dose of Ad-delta-huPA plus Ad-MMP8 (3 × 10¹¹and 1.5 × 10¹¹vp/Kg, respectively) or with Ad-beta-Gal (4.5 × 10¹¹) and were killed after 2, 4, 6, 8 and 10 days. Then, liver and serum were collected. An additional set of cirrhotic animals injected with combined gene therapy was also monitored for their probability of survival.</p> <p>Results</p> <p>Only the cirrhotic animals treated with therapeutical genes (Ad-delta-huPA+Ad-MMP-8) showed improvement in liver fibrosis. These results correlated with hydroxyproline determinations. A significant decrement in alpha-SMA and TGF-beta1 gene expression was also observed. Cirrhotic rats treated with Ad-delta-huPA plus Ad-MMP8 had a higher probability of survival at 60 days with respect to Ad-beta-Gal-injected animals.</p> <p>Conclusion</p> <p>A single administration of Ad-delta-huPA plus Ad-MMP-8 is efficient to induce fibrosis regression and increase survival in experimental liver fibrosis.</p

Chemically induced liver regeneration is characterized by specific IL-6 gene expression

IL-6 and TNF � have been shown as important cytokines in liver regeneration induced in partially hepatectomized rats. Nonetheless, IL-6 gene expression in the course of chemically induced hepatic regeneration, resembling what occurs in humans infected by hepatitis virus in acute manner, remains obscure. To gain an insight on this matter we determined IL-6 and TNF � gene expression in Wistar rats after acute and chronic liver intoxication with CCl 4 and/or turpentine. We used a semiquantitative method of RT-PCR to analyze cytokine gene expression and, quite interestingly, IL-6 was detected only at 24 h after acute damage as opposed to TNF � expression that was increased from 6 to 48 h after acute injury. A single intradermally-injected dose of turpentine did not suffice to induce IL-6 gene expression at any studied times, but, as expected, turpentine-treated animals showed decreased albumin mRNA transcripts as compared with the control rats. Furthermore, livers from cirrhotic animals did not show detectable IL-6 gene transcripts, but, IL-6 expression re-appeared in cirrhotic rats treated with an additional acute CCl 4 dose, indicating that IL-6 is a critica

El factor de crecimiento transformante beta como blanco terapéutico Transforming growth factor-beta as a therapeutic target

El factor de crecimiento transformante beta (TGF-beta) es una familia de proteínas que incluye al TGF-beta, activinas y a la proteína morfogénica de hueso (BMP, por sus siglas en inglés), citocinas que son secretadas y se relacionan estructuralmente en diferentes especies de metazoarios. Los miembros de la familia del TGF-beta regulan diferentes funciones celulares como proliferación, apoptosis, diferenciación, migración, y tienen un papel clave en el desarrollo del organismo. El TGF-beta está implicado en varias patologías humanas, incluyendo desórdenes autoinmunes y vasculares, así como enfermedades fibróticas y cáncer. La activación del receptor del TGF-beta propicia su fosforilación en residuos de serina/treonina y dispara la fosforilación de proteínas efectoras intracelulares (smad), que una vez activas se translocan al núcleo para inducir la transcripción de genes blanco, y así regular procesos y funciones celulares. Se están desarrollando novedosas estrategias terapéuticas encaminadas a corregir las alteraciones presentes en patologías que involucran al TGF-beta como actor principal.<br>Transforming growth factor-beta (TGF-beta) family members include TGF-beta, activins, and bone morphogenetic proteins (BMP). These proteins are structurally related cytokines secreted in diverse Metazoans. TGF-beta family members regulate cellular functions such as proliferation, apoptosis, differentiation, and migration, and play an important role in organism development. Deregulated TGF-beta family signaling participates in various human pathologies including auto-immune diseases, vascular disorders, fibrotic disease, and cancer. Ligand-induced activation of TGF-beta family receptors with intrinsic serine/threonine kinase activity, triggers phosphorylation of the intracellular effectors of TGF-beta signaling, the Smads proteins. Once these proteins are activated they translocate into the nucleus, where they induce transcription of target genes and regulate cellular processes and functions. Novel therapeutic strategies are currently being developed to correct alterations in pathologies that involve TGF-beta as the main mediator

El factor de crecimiento transformante B como blanco terapéutico

El factor de crecimiento transformante b (TGF- b) es una familia de proteínas que incluye al TGF- b, activinas y a la proteína morfogénica de hueso (BMP, por sus siglas en inglés), citocinas que son secretadas y se relacionan estructuralmente en diferentes especies de metazoarios. Los miembros de la familia del TGF- b regulan diferentes funciones celulares como proliferación, apoptosis, diferenciación, migración, y tienen un papel clave en el desarrollo del organismo. El TGF- b está implicado en varias patologías humanas, incluyendo desórdenes autoinmunes y vasculares, así como enfermedades fibróticas y cáncer. La activación del receptor del TGF- b propicia su fosforilación en residuos de serina/treonina y dispara la fosforilación de proteínas efectoras intracelulares (smad), que una vez activas se translocan al núcleo para inducir la transcripción de genes blanco, y así regular procesos y funciones celulares. Se están desarrollando novedosas estrategias terapéuticas encaminadas a corregir las alteraciones presentes en patologías que involucran al TGF- b como actor principal. El texto completo en inglés de este artículo está disponible en: http:// www.insp.mx/salud/index.htm