title: Transforming growth factor-β signaling promotes pulmonary hypertension caused by Schistosoma mansoni.
abstract: BACKGROUND
  The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor-β (TGF-β) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease.
  
  
  RESULTS
  Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for ≈60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF-β signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF-β signaling in their remodeled pulmonary arteries.
  
  
  CONCLUSIONS
  Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF-β signaling.
authors: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine (B.B.G., J.C., L.G., J.P., E.D., L.D., T.T., L.S., N.D., R.W.V.) and Department of Pathology (X.-J.W.), Anschutz Medical Campus, Aurora, CO; Pulmonary Vascular Research Institute (B.B.G., A.B., H.C.C., G.B., R.M.T.); Memorial S. Jose Hospital, Universidade de Pernambuco in Recife, Recife, Brazil (A.B.); Division of Cardiology, University of Pittsburgh, Pittsburgh, PA (H.C.C.); School of Pharmacy, University of Kent, Kent, UK (G.B.); and Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (T.A.W.).
authors: Brian B
authors: BB
authors: Graham
authors: Jacob
authors: J
authors: Chabon
authors: Liya
authors: L
authors: Gebreab
authors: Jennifer
authors: J
authors: Poole
authors: Elias
authors: E
authors: Debella
authors: Laura
authors: L
authors: Davis
authors: Takeshi
authors: T
authors: Tanaka
authors: Linda
authors: L
authors: Sanders
authors: Nina
authors: N
authors: Dropcho
authors: Angela
authors: A
authors: Bandeira
authors: R William
authors: RW
authors: Vandivier
authors: Hunter C
authors: HC
authors: Champion
authors: Ghazwan
authors: G
authors: Butrous
authors: Xiao-Jing
authors: XJ
authors: Wang
authors: Thomas A
authors: TA
authors: Wynn
authors: Rubin M
authors: RM
authors: Tuder
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000469:parasitology*; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011652:Pulmonary Circulation / Q000502:physiology; D012550:Schistosoma mansoni; D012555:Schistosomiasis mansoni / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D016212:Transforming Growth Factor beta
keywords: hypertension, pulmonary; schistosomiasis; transforming growth factor beta
references: Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L665-72
references: 12959926
references: Semin Respir Crit Care Med. 2009 Aug;30(4):376-85
references: 19634077
references: Cancer Res. 1976 Oct;36(10):3761-5
references: 986241
references: Nature. 1998 Jun 25;393(6687):786-90
references: 9655392
references: Am J Respir Crit Care Med. 2011 Jul 1;184(1):116-23
references: 21471108
references: Nature. 2008 Mar 20;452(7185):296
references: 18354470
references: Chest. 2010 Jun;137(6 Suppl):20S-29S
references: 20522577
references: Infect Immun. 1999 Mar;67(3):1187-93
references: 10024559
references: Eur Respir J. 2003 Aug;22(2):358-63
references: 12952274
references: J Exp Med. 2008 Feb 18;205(2):361-72
references: 18227220
references: Lancet Infect Dis. 2006 Jul;6(7):411-25
references: 16790382
references: Circulation. 2008 Oct 21;118(17):1758-66
references: 18936338
references: Science. 2011 Jun 10;332(6035):1284-8
references: 21566158
references: Am J Respir Crit Care Med. 2008 Apr 15;177(8):896-905
references: 18202349
references: J Infect Dis. 2002 Jan 1;185(1):98-105
references: 11756987
references: Nat Genet. 2000 Sep;26(1):81-4
references: 10973254
references: J Clin Invest. 2008 Aug;118(8):2722-32
references: 18618014
references: Arq Bras Cardiol. 2012 Sep;99(3):789-96
references: 22836358
references: Circ Res. 2007 Mar 30;100(6):923-9
references: 17332430
references: Am J Respir Crit Care Med. 2004 Dec 15;170(12):1340-8
references: 15361368
references: Am J Pathol. 2010 Sep;177(3):1549-61
references: 20671265
references: Eur Respir Rev. 2010 Mar;19(115):46-54
references: 20956165
references: J Immunol. 2004 Sep 15;173(6):4020-9
references: 15356151
references: J Clin Invest. 2011 Nov;121(11):4548-66
references: 22005303
references: Parasite Immunol. 2009 Apr;31(4):163-76
references: 19292768