High Mobility Group Box 1 Contributes to the Pathogenesis of Experimental Pulmonary Hypertension via Activation of Toll-like Receptor 4

Eileen M Bauer,Suzy A Comhair,Philip M Bauer,Timothy R Billiar,Han Zheng,Ferhaan Ahmad,Serpil C Erzurum,David Ishizawar,Richard Shapiro

doi:10.2119/molmed.2012.00283

Eileen M Bauer, Suzy A Comhair + Show 7 more

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https://doi.org/10.2119/molmed.2012.00283

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Abstract

Survival rates for patients with pulmonary hypertension (PH) remain low, and our understanding of the mechanisms involved are incomplete. Here we show in a mouse model of chronic hypoxia (CH)-induced PH that the nuclear protein and damage-associate molecular pattern molecule (DAMP) high mobility group box 1 (HMGB1) contributes to PH via a Toll-like receptor 4 (TLR4)-dependent mechanism. We demonstrate extranuclear HMGB1 in pulmonary vascular lesions and increased serum HMGB1 in patients with idiopathic pulmonary arterial hypertension. The increase in circulating HMGB1 correlated with mean pulmonary artery pressure. In mice, we similarly detected the translocation and release of HMGB1 after exposure to CH. HMGB1-neutralizing antibody attenuated the development of CH-induced PH, as assessed by measurement of right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling and endothelial activation and inflammation. Genetic deletion of the pattern recognition receptor TLR4, but not the receptor for advanced glycation end products, likewise attenuated CH-induced PH. Finally, daily treatment of mice with recombinant human HMGB1 exacerbated CH-induced PH in wild-type (WT) but not Tlr4(-/-) mice. These data demonstrate that HMGB1-mediated activation of TLR4 promotes experimental PH and identify HMGB1 and/or TLR4 as potential therapeutic targets for the treatment of PH.

Highlights

Pulmonary hypertension (PH) is a devastating disease characterized by a sustained increase in pulmonary arterial pressure
Cell Culture Human pulmonary artery endothelial cells (HPAECs), human pulmonary artery smooth muscle cells (HPASMCs) and cell media were from Lonza
To identify a role for high mobility group box 1 (HMGB1) in PH, we initially sought to determine whether HMGB1 is mobilized from the nucleus to the extracellular milieu, where it can act as a damageassociate molecular pattern molecule (DAMP)

Summary

Introduction

Pulmonary hypertension (PH) is a devastating disease characterized by a sustained increase in pulmonary arterial pressure. PH can be idiopathic, familial, associated with connective tissue disease or a result of drug or toxin exposure [1]. Patients with these various forms of PH exhibit similar clinical, functional and hemodynamic characteristics and poor survival [2,3,4,5]. While use of drugs promoting vasodilation leads to improvements in functional capacity and modest decreases in pulmonary artery pressure, recent metaanalysis of controlled trials using these agents demonstrated only limited benefit in terms of mortality [7,8]

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