obeticholic-acid and Pulmonary-Fibrosis

Bile acids act as steroid hormones, controlling lipid, glucose and energy metabolism, as well as inflammation and fibrosis. Their actions are implemented through activation of nuclear (FXR, VDR, PXR) and membrane G protein-coupled (TGR5, S1PR2) receptors. Areas covered: This review discusses the potential of FXR and TGR5 as therapeutic targets in the treatment of pulmonary disorders linked to metabolism and/or inflammation. Obeticholic acid (OCA) is the most clinically advanced bile acid-derived agonist for FXR-mediated anti-inflammatory and anti-fibrotic effects. It therefore represents an attractive pharmacological approach for the treatment of lung conditions characterized by vascular and endothelial dysfunctions. Expert opinion: Inflammation, vascular remodeling and fibrotic processes characterize the progression of pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). These processes are only partially targeted by the available therapeutic options and still represent a relevant medical need. The results hereby summarized demonstrate OCA efficacy in preventing experimental lung disorders, i.e. monocrotaline-induced PAH and bleomycin-induced fibrosis, by abating proinflammatory and vascular remodeling progression. TGR5 is also expressed in the lung, and targeting the TGR5 pathway, using the TGR5 agonist INT-777 or the dual FXR/TGR5 agonist INT-767, could also contribute to the treatment of pulmonary disorders mediated by inflammation and fibrosis.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Drug Design; Humans; Inflammation; Lung Diseases; Molecular Targeted Therapy; Pulmonary Fibrosis; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled

We recently demonstrated a protective effect of the farnesoid X receptor agonist obeticholic acid (OCA) in rat models of bleomycin-induced pulmonary fibrosis (PF). Aim of the present study was to investigate whether the positive effects of OCA treatment are apparent also on ongoing bleomycin-induced PF, i.e., after 2 weeks of bleomycin administration.. Bleomycin-induced PF rats were treated 2 weeks after bleomycin administration with OCA or pirfenidone for two additional weeks. Pulmonary function test was performed at 2 and 4 weeks in all experimental groups. At the same time points, lung morphological features and mRNA expression profile of genes related to fibrosis, inflammation and epithelial-mesenchymal transition were also assessed.. After 2 weeks, bleomycin significantly increased the pressure at the airway opening (PAO), a functional parameter related to fibrosis-induced lung stiffness, and induced diffuse lung interstitium fibrosis, with upregulation of inflammation (IL1β, MCP1) and tissue remodeling (COL1A1, COL3A1, ET1, MMP7, PDGFa, αSMA, SNAI1) markers. At week four, a further increase of lung fibrosis and PAO was observed, accompanied by upregulation of extracellular matrix-related mRNA expression. OCA administration, even after the establishment of PF, significantly improved pulmonary function, normalizing PAO, and reverted the bleomycin-induced lung alterations, with significant reduction of markers of inflammation (CD206, COX2, HIF1, IL1β, MCP1), epithelial proliferation (CTGF, PDGFa) and fibrosis (COL1A1, COL3A1, ET1, FN1, MMPs, αSMA, SNAIs, TGFβ1, TIMPs). Results with OCA were similar or superior to those obtained with pirfenidone.. In conclusion, our results demonstrate a significant therapeutic effect of OCA in already established PF.

Topics: Animals; Antibiotics, Antineoplastic; Biomarkers; Bleomycin; Chenodeoxycholic Acid; Disease Models, Animal; Epithelial-Mesenchymal Transition; Male; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley

Activation of the farnesoid X receptor (FXR), a member of the nuclear receptor steroid superfamily, leads to anti-inflammatory and anti-fibrotic effects in several tissues, including the lung. We have recently demonstrated a protective effect of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) in rat models of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and bleomycin-induced pulmonary fibrosis. The aim of the present study was to investigate whether the positive effects of OCA treatment could be exerted also in established MCT-induced PAH, i.e., starting treatment 2 weeks after MCT administration.. Rats with MCT-induced PAH were treated, 2 weeks after MCT administration, with OCA or tadalafil for two additional weeks. Pulmonary functional tests were performed at week 2 (before treatment) and four (end of treatment). At the same time points, lung morphological features and expression profile of genes related to smooth muscle relaxation/contraction and tissue remodeling were also assessed.. 2 weeks after MCT-induced injury, the treadmill resistance (a functional parameter related to pulmonary hypertension) was significantly decreased. At the same time point, we observed right ventricular hypertrophy and vascular remodeling, with upregulation of genes related to inflammation. At week 4, we observed a further worsening of the functional and morphological parameters, accompanied by dysregulation of inflammatory and extracellular matrix markers mRNA expression. Administration of OCA (3 or 10 mg/kg/day), starting 2 weeks after MCT-induced injury, significantly improved pulmonary function, effectively normalizing the exercise capacity. OCA also reverted most of the lung alterations, with a significant reduction of lung vascular wall thickness, right ventricular hypertrophy, and restoration of the local balance between relaxant and contractile pathways. Markers of remodeling pathways were also normalized by OCA treatment. Notably, results with OCA treatment were similar, or even superior, to those obtained with tadalafil, a recently approved treatment for pulmonary hypertension.. The results of this study demonstrate a significant therapeutic effect of OCA in established MCT-induced PAH, improving exercise capacity associated with reduction of right ventricular hypertrophy and lung vascular remodeling. Thus, OCA dosing in a therapeutic protocol restores the balance between relaxant and contractile pathways in the lung, promoting cardiopulmonary protective actions in MCT-induced PAH.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Chenodeoxycholic Acid; Disease Models, Animal; Hypertension, Pulmonary; Male; Monocrotaline; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear

Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development in liver, kidney and intestine in multiple disease models. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the protective effects of OCA treatment (3 or 10mg/kg/day) on inflammation, tissue remodeling and fibrosis in the bleomycin-induced pulmonary fibrosis rat model. Effects of OCA treatment on morphological and molecular alterations of the lung, as well as remodeling of the alveoli and the right ventricle were also evaluated. Lung function was assessed by measuring airway resistance to inflation. In the acute phase (7days), bleomycin promoted an initial thickening and fibrosis of the lung interstitium, with upregulation of genes related to epithelial proliferation, tissue remodeling and hypoxia. At 28days, an evident increase in the deposition of collagen in the lungs was observed. This excessive deposition was accompanied by an upregulation of transcripts related to the extracellular matrix (TGFβ1, SNAI1 and SNAI2), indicating lung fibrosis. Administration of OCA protected against bleomycin-induced lung damage by suppressing molecular mechanisms related to epithelial-to-mesenchymal transition (EMT), inflammation and collagen deposition, with a dose-dependent reduction of proinflammatory cytokines such as IL-1β and IL-6, as well as TGF-β1 and SNAI1 expression. Pirfenidone, a recently approved treatment for idiopathic pulmonary fibrosis (IPF), significantly counteracted bleomycin-induced pro-fibrotic genes expression, but did not exert significant effects on IL-1β and IL-6. OCA treatment in bleomycin-challenged rats also improved pulmonary function, by effectively normalizing airway resistance to inflation and lung stiffness in vivo. Results with OCA were similar, or even superior, to those obtained with pirfenidone. In conclusion, our results suggest an important protective effect of OCA against bleomycin-induced lung fibrosis by blunting critical mediators in the pathogenesis of IPF.

Topics: Airway Remodeling; Animals; Bleomycin; Chenodeoxycholic Acid; Collagen; Disease Models, Animal; Fibrosis; Gene Expression Profiling; Immunohistochemistry; Inflammation; Lung; Male; Pulmonary Alveoli; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Ventricular Remodeling