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Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis

2017; Wiley; Volume: 174; Issue: 19 Linguagem: Inglês

10.1111/bph.13947

1476-5381

Scott D. Collum, Ning‐Yuan Chen, Adriana M. Hernandez, Ankit Hanmandlu, Heather Sweeney, Tinne C. J. Mertens, Tingting Weng, Fayong Luo, Jose G. Molina, Jonathan Davies, Ian Horan, Nicholas W. Morrell, Javier Amione‐Guerra, Odeaa Aljabbari, Keith A. Youker, Wenchao Sun, Jayakumar Rajadas, Paul L. Bollyky, Bindu Akkanti, Soma Jyothula, Neeraj Sinha, Ashrith Guha, Harry Karmouty‐Quintana,

Chronic Obstructive Pulmonary Disease (COPD) Research

Group III pulmonary hypertension (PH) is a highly lethal and widespread lung disorder that is a common complication in idiopathic pulmonary fibrosis (IPF) where it is considered to be the single most significant predictor of mortality. While increased levels of hyaluronan have been observed in IPF patients, hyaluronan-mediated vascular remodelling and the hyaluronan-mediated mechanisms promoting PH associated with IPF are not fully understood.Explanted lung tissue from patients with IPF with and without a diagnosis of PH was used to identify increased levels of hyaluronan. In addition, an experimental model of lung fibrosis and PH was used to test the capacity of 4-methylumbeliferone (4MU), a hyaluronan synthase inhibitor to attenuate PH. Human pulmonary artery smooth muscle cells (PASMC) were used to identify the hyaluronan-specific mechanisms that lead to the development of PH associated with lung fibrosis.In patients with IPF and PH, increased levels of hyaluronan and expression of hyaluronan synthase genes are present. Interestingly, we also report increased levels of hyaluronidases in patients with IPF and IPF with PH. Remarkably, our data also show that 4MU is able to inhibit PH in our model either prophylactically or therapeutically, without affecting fibrosis. Studies to determine the hyaluronan-specific mechanisms revealed that hyaluronan fragments result in increased PASMC stiffness and proliferation but reduced cell motility in a RhoA-dependent manner.Taken together, our results show evidence of a unique mechanism contributing to PH in the context of lung fibrosis.