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Administration of Bilins and High-Dose Biotin May Replicate the Beneficial Impact of Heme Oxygenase-1 Induction on Pathogenic Fibrosis

By Mark F. Mccarty

Abstract

Clinical fibrotic syndromes are usually driven by excessive transforming growth factor-beta (TGF-beta) activity. Heme oxygenase-1 (HO-1), which is induced by TGF-beta in many tissues, has antifibrotic effects which are at least partially attributable to down-regulation of TGF-beta signal transduction. This down-regulation is mediated by bilirubin – a physiological inhibitor of NADPH oxidase that suppresses the oxidant stress required for optimal TGF-beta activity – and by carbon monoxide, which acts via guanylate cyclase, cGMP, and protein kinase G to inhibit the nuclear translocation of phosphorylated Smads while also impeding TGF-beta activation by blocking thrombospondin-1 transcription. It may be feasible to mimic these protective effects of HO-1 in clinical fibrotic syndromes by administering bilins (biliverdin or phycocyanobilin) and high-dose biotin – the former can function as clinical NADPH oxidase inhibitors, whereas the latter stimulates guanylate cyclase activity. This strategy may prove useful in the prevention and management of clinical fibrotic syndromes in which TGF-beta activity plays a central mediating role – likely including hepatic cirrhosis, glomerulosclerosis, interstitial fibrosis, ventricular hypertrophy, atrial fibrosis with fibrillation, pulmonary hypertension, cystic fibrosis, idiopathic pulmonary fibrosis, asthma, pancreatic fibrosis, scleroderma, and fibrostenosis in Crohn’

Year: 2013
OAI identifier: oai:CiteSeerX.psu:10.1.1.319.4517
Provided by: CiteSeerX
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