Research Area K: Pulmonary hypertension associated with infectious diseases and high altitude
| Research Area Leaders | |
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Dept. Internal Medicine, Medical Clinic II Klinikstrasse 33 35392 Giessen |
Prof. Dr. Martin R. Wilkins Dept. of Experimental Medicine2N7 Commonwealth Building Hammersmith Campus London, UK |
| Faculty involved | ||||
|---|---|---|---|---|
| T. Braun | G. Butrous | A. Crosby | S. Dimmeler | D.W. Dunne |
| H.A. Ghofrani | F. Grimminger | J. Lohmeyer | N.W. Morrell | S.S. Pullamsetti |
| R.T. Schermuly | W. Seeger | R. Voswinckel | N. Weissmann | J. Wharton |
| M.R. Wilkins | A.M. Zeiher | L. Zhao | ||
Summary
Area K is a novel initiative aimed at institutionalising and promoting collaborative research between the ECCPS, Imperial College London (ICL) and associated partners (Cambridge University, the global Pulmonary Vascular Research Institute; PVRI). Our goal is to pool resources to combat states of pulmonary hypertension (PH) which represent major public health problems in resourcepoor areas of the world. We will focus on three major diseases
- Schistosomiasis, which is the third leading endemic parasitic disease in the world, with >300 million infected individuals, 5-7% of which develop PH, which may progress even under antiparasitic treatment.
- Human immunodeficiency virus (HIV) infection (>40 million people affected worldwide, with >50 % in Sub-Saharan Africa) increases the risk for PH development >1000-fold, a statistic that remains unchanged even under combination antiretroviral therapy, and
- High altitude (HA)- PH. More than 140 million people live at an altitude of >2500 m, with up to 5 % of them developing chronic mountain sickness/PH. Studies will include molecular profiling and identification of signatures in diseased human and experimental lungs and cultured human lung cells (transcriptome, miRome, exome, proteome), hypothesis-generating and therapeutic studies in preclinical models, and genome-wide association studies. We aim to develop novel anti-inflammatory strategies for antiremodelling/prevention of PH, to decipher the molecular pathogenesis of Schistosoma mansoni (SM-PH) and HIV-induced PH (HIV-PH), to identify biomarkers for early bedside detection of SMPH and HIV-PH, to identify genes underlying susceptibility versus resistance to hypoxia and perform early clinical trials to combat SM-PH, HIV-PH and HA-PH in regions severely affected by these diseases.
Most relevant publications preceding the foundation of the new international Area K
1. Crosby A, Jones FM, Kolosionek E, Southwood M, Purvis I, Soon E, Butrous G, Dunne DW, Morrell NW. Praziquantel Reverses Pulmonary Hypertension and Vascular Remodeling in Murine Schistosomiasis. Am J Respir Crit Care Med. Jun 9. [Epub ahead of print]
2. Pullamsetti SS, Savai R, Dumitrascu R, Dahal BK, Wilhelm J, Konigshoff M, Zakrzewicz D, Ghofrani HA, Weissmann N, Eickelberg O, Guenther A, Leiper J, Seeger W, Grimminger F, Schermuly RT. The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis. Sci Transl Med J15;3:87ra53, 2011
3. Rhodes CJ, Howard LS, Busbridge M, Ashby D, Kondili E, Gibbs, JS, Wharton J, Wilkins MR. Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension clinical prevalence, outcomes, and mechanistic insights. J Am Coll Cardiol 58:300-9, 2011
4. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 8:443-55, 2011
5. Crosby A, Jones FM, Southwood M, Stewart S, Schermuly RT, Butrous G, Dunne DW, Dahal BK, Cornitescu T, Tretyn A, Pullamsetti SS, Kosanovic D, Dumitrascu R, Ghofrani HA, Weissmann N, Voswinckel R, Banat GA, Seeger W, Grimminger F, Schermuly RT. Role of Epidermal Growth Factor Inhibition in Experimental Pulmonary Hypertension. Am J Respir Crit Care Med 181:158-67, 2011
6. Abdul-Salam VB, Wharton J, Cupitt J, Berryman M, Edwards RJ, Wilkins MR. Proteomic analysis of lung tissues from patients with pulmonary arterial hypertension. Circulation 122:2058-67, 2010
7. Crosby A, Jones FM, Southwood M, Stewart S, Schermuly R, Butrous G, Dunne DW, Morrell NW. Pulmonary vascular remodeling correlates with lung ova and cytokines in murine schistosomiasis. Am J Respir Crit Care Med 181:279-88, 2010
8. Durrington HJ, Upton PD, Hoer S, Boname J, Dunmore BJ, Yang J, Crilley TK, Butler LM, Blackbourn DJ, Nash GB, Lehner PJ, Morrell NW. Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II. J Biol Chem 285:37641-9, 2010
9. Graham BB, Mentink-Kane MM, El-Haddad H, Purnell S, Zhang L, Zaiman A, Redente EF, Riches DW, Hassoun PM, Bandeira A, Champion HC, Butrous G, Wynn TA, Tuder RM.Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am J Pathol 177: 1549-61, 2010
10. Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, Walker C, Budd DC, Pepke-Zaba J, Morrell NW. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122:920-7, 2010
11. Wilkins MR, Ali O, Bradlow W, Wharton J, Taegtmeyer A, Rhodes CJ, Ghofrani HA, Howard L, Nihoyannopoulos P, Mohiaddin RH, Gibbs JS; Simvastatin Pulmonary Hypertension Trial (SiPHT) Study Group.Simvastatin as a treatment for pulmonary hypertension trial. Am J Respir Crit Care Med 181:1106-13, 2010
12. Yang J, Li X, Al-Lamki RS, Southwood M, Zhao J, Lever AM, Grimminger F, Schermuly RT, Morrell NW. Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. Circ Res 107:252-62, 2010
13. Dahal BK, Cornitescu T, Tretyn A, Pullamsetti SS, Kosanovic D, Dumitrascu R, Ghofrani HA, Weissmann N, Voswinckel R, Banat GA, Seeger W, Grimminger F, Schermuly RT. Role of Epidermal Growth Factor Inhibition in Experimental Pulmonary Hypertension. Am J Respir Crit Care Med 181: 158-67, 2009
14. Königshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, Günther A, Eickelberg O. WNT1-inducible signalling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest 119: 772-87, 2009
15. Long L, Crosby A, Yang X, Southwood M, Upton PD, Kim DK, Morrell NW. Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease. Circulation 119:566-76, 2009
16. Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation 118:1758-66, 2008
17. Ghofrani HA, Wilkins MW, Rich S. Uncertainties in the diagnosis and treatment of pulmonary arterial hypertension. Circulation 118:1195-201, 2008
18. Diller GP, van Eijl S, Okonko DO, Howard LS, Ali O, Thum T, Wort SJ, Bedard E, Gibbs JS, Bauersachs J, Hobbs AJ, Wilkins MR, Gatzoulis MA, Wharton J. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 117:3020-30, 2008
19. Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, Schellong S, Urashima T, Wang L, Morrell NW, Rabinovitch M. An antiproliferative BMP- 2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 118:1846-57, 2008
20. Yang J, Davies RJ, Southwood M, Long L, Yang X, Sobolewski A, Upton PD, Trembath RC, Morrell NW. Mutations in bone morphogenetic protein type II receptor cause dysregulation of Id gene expression in pulmonary artery smooth muscle cells: implications for familial pulmonary arterial hypertension. Circ Res 102:1212-21, 2008
21. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 5:689-702, 2006
22. Kalmyrzaev B, Aldashev A, Khalmatov M, Polupanov A, Jumagulova A, Mamanova L, Wilkins MR, Town M. Genome-wide scan for premature hypertension supports linkage to chromosome 2 in a large Kyrgyz family. Hypertension 48:908-13, 2006
23. Voswinckel R, Ghofrani HA, Grimminger F, Seeger W, Olschewski H. Inhaled trepostinil for treatment of chronic pulmonary arterial hypertension. Ann Intern Med 144:149-50, 2006
24. Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, Olschewski A, Storch U, Schnitzler M, Ghofrani HA, Schermuly RT, Pinkenburg O, Seeger W, Grimminger F, Gudermann T. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci USA 103:19093-98, 2006
25. Ghofrani HA, Seeger W, Grimminger F: Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 353:1412-1413, 2005 IF 53,484
26. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F: Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115:2811-21, 2005
27. Spragg RG, Lewis JF, Walmrath HD, Johannigman J, Bellingan G, Laterre PF, Witte MC, Richards GA, Rippin G, Rathgeb F, Hafner D, Taut FJ, Seeger W: Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 351:884-92, 2004
28. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 360:895-900, 2002
29. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, Nikkho S, Speich R, Hoeper MM, Behr J, Winkler J, Sitbon O, Popov W, Ghofrani HA, Manes A, Kiely DG, Ewert R, Meyer A, Corris PA, Delcroix M, Gomez-Sanchez M, Siedentop H, Seeger W: Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 347:322-29, 2002
30. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW. Clinical and molecular genetic features of pulmonary hypertension in hereditary hemorrhagic telangiectasia. N Engl J Med 345:325-34, 2001