HYDAMTIQ, a selective PARP‐1 inhibitor, improves bleomycin‐induced lung fibrosis by dampening the TGF‐β/SMAD signalling pathway

Abstract

Idiopathic pulmonary fibrosis is a severe disease characterized by excessive myofibroblast proliferation, extracellular matrix and fibrils deposition, remodelling of lung parenchyma and pulmonary insufficiency. Drugs able to reduce disease progression are available, but therapeutic results are unsatisfactory; new and safe treatments are urgently needed. Poly(ADP‐ribose) polymerases‐1 (PARP‐1) is an abundant nuclear enzyme involved in key biological processes: DNA repair, gene expression control, and cell survival or death. In liver and heart, PARP‐1 activity facilitates oxidative damage, collagen deposition and fibrosis development. In this study, we investigated the effects of HYDAMTIQ, a potent PARP‐1 inhibitor, in a murine model of lung fibrosis. We evaluated the role of PARP on transforming growth factor‐β (TGF‐β) expression and TGF‐β/SMAD signalling pathway in lungs. Mice were intratracheally injected with bleomycin and then treated with either vehicle or different doses of HYDAMTIQ for 21 days. Airway resistance to inflation and lung static compliance, markers of lung stiffness, were assayed. Histochemical and biochemical parameters to evaluate TGF‐β/SMAD signalling pathway with alpha‐smooth muscle actin (αSMA) deposition and the levels of a number of inflammatory markers (tumour necrosis factor‐α, interleukin‐1β, iNOS and COX‐2) were performed. Bleomycin administration increased lung stiffness. It also increased lung PARP activity, TGF‐β levels, pSMAD3 expression, αSMA deposition and content of inflammatory markers. HYDAMTIQ attenuated all the above‐mentioned physiological, biochemical and histopathological markers. Our findings support the proposal that PARP inhibitors could have a therapeutic potential in reducing the progression of signs and symptoms of the disease by decreasing TGF‐β expression and the TGF‐β/SMAD transduction pathway.

Reduced Susceptibility to Sugar‐Induced Metabolic Derangements and Impairments of Myocardial Redox Signaling in Mice Chronically Fed with D‐Tagatose when Compared to Fructose

“…HbA1C and proteinuria were measured in plasma and urine, respectively, by using standard analysis kits. The plasma leptin level and inflammatory profile (TNF- α , IL-1 β , and IL-6) were determined, as previously described [ 25 ] using enzyme-linked immunosorbent assay (ELISA) kits.…”

“…DNA isolation from cardiac tissue homogenates was performed according to Collino et al [ 25 , 26 ]. Samples of DNA extract were used for 8-hydroxy-2′-deoxyguanosine (8-OHdG) determination using an ELISA kit (JalCA, Shizuoka, Japan), following the instructions provided by the manufacturer.…”

Curcumin and paclitaxel induce cell death in breast cancer cell lines

“…PARP is a target of caspase protease activity and is also associated with apoptosis. When PARP detects DNA damage, it is auto-modified and recruits repair factors to the DNA damage sites (15,16). Defects in DNA repair lead to genomic instability and play a critical role in cancer development.…”

MicroRNA 200b is upregulated in the lungs of fetal rabbits with surgically induced diaphragmatic hernia

“…We could also investigate accumulation in tracheal fluids. An antagonist study giving miR‐200b inhibitors to the pregnant doe in early gestation or blocking downstream effectors of the SMAD pathway in operated fetuses would also clarify the role of miR‐200b in the hypoplastic lung . Evaluating the other members of the miR‐200b family, particularly those also located on chromosome 1, would enhance our understanding of their role in the hypoplastic lung.…”