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Molecular Medicine

, Volume 18, Issue 12, pp 1509–1518 | Cite as

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

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

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.

Notes

Acknowledgments

We thank Kevin Tracey (North Shore-LIJ Health System, Feinstein Institute for Medical Research) for providing the HMGB1 neutralizing antibody. We thank Suchitra Barge, Michael Lotze and Lisa Butterfield (University of Pittsburgh) for assistance in obtaining control patient samples. Some of the IPAH patient samples were provided by Cooperative Human Tissue Network, Southern Division, The University of Alabama at Birmingham, under the Pulmonary Hypertension Breakthrough Initiative (PHBI). Funding for the PHBI was provided by the Cardiovascular Medical Research and Education Fund. This work was supported by grants to PM Bauer (R01-HL085134 and NIH R03-HL110794), SC Erzurum (R01-HL60917), TR Billiar (P50-GM53789) and EM Bauer (T32-098036).

Supplementary material

10020_2012_18121509_MOESM1_ESM.pdf (3.7 mb)
High Mobility Group Box 1 Contributes to the Pathogenesis of Experimental Pulmonary Hypertension via Activation of Toll-like Receptor 4

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Authors and Affiliations

  • Eileen M Bauer
    • 1
  • Richard Shapiro
    • 1
  • Han Zheng
    • 1
  • Ferhaan Ahmad
    • 2
    • 3
    • 4
  • David Ishizawar
    • 2
  • Suzy A Comhair
    • 5
  • Serpil C Erzurum
    • 5
  • Timothy R Billiar
    • 1
  • Philip M Bauer
    • 1
    • 4
    • 6
  1. 1.Department of SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of Human GeneticsUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Vascular Medicine InstituteUniversity of Pittsburgh School of MedicinePittsburghUSA
  5. 5.Department of PathobiologyLerner Research Institute, and the Respiratory Institute, Cleveland ClinicClevelandUSA
  6. 6.Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA

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