Advertisement

 

 

Inhibition of Hyaluronan Synthesis Attenuates Pulmonary Hypertension Associated with Lung Fibrosis.

Inhibition of Hyaluronan Synthesis Attenuates Pulmonary Hypertension Associated with Lung Fibrosis.
Author Information (click to view)

Collum SD, Chen NY, Hernandez AM, Hanmandlu A, Sweeney H, Mertens TCJ, Weng T, Luo F, Molina JG, Davies J, Horan IP, Morrell NW, Amione-Guerra J, Al-Jabbari O, Youker K, Sun W, Rajadas J, Bollyky PL, Akkanti BH, Jyothula S, Sinha N, Guha A, Karmouty-Quintana H,


Collum SD, Chen NY, Hernandez AM, Hanmandlu A, Sweeney H, Mertens TCJ, Weng T, Luo F, Molina JG, Davies J, Horan IP, Morrell NW, Amione-Guerra J, Al-Jabbari O, Youker K, Sun W, Rajadas J, Bollyky PL, Akkanti BH, Jyothula S, Sinha N, Guha A, Karmouty-Quintana H, (click to view)

Collum SD, Chen NY, Hernandez AM, Hanmandlu A, Sweeney H, Mertens TCJ, Weng T, Luo F, Molina JG, Davies J, Horan IP, Morrell NW, Amione-Guerra J, Al-Jabbari O, Youker K, Sun W, Rajadas J, Bollyky PL, Akkanti BH, Jyothula S, Sinha N, Guha A, Karmouty-Quintana H,

Advertisement

British journal of pharmacology 2017 07 08() doi 10.1111/bph.13947
Abstract
BACKGROUND AND PURPOSE
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.

EXPERIMENTAL APPROACH
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.

KEY RESULTS
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.

CONCLUSIONS AND IMPLICATIONS
Taken together, our results show evidence of a unique mechanism contributing to PH in the context of lung fibrosis.

Submit a Comment

Your email address will not be published. Required fields are marked *

twelve − 4 =

[ HIDE/SHOW ]