Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling.
The mechanisms underlying schistosomiasis-induced pulmonary hypertension (PH), one of the most common causes of PH worldwide, remain unclear. We sought to determine whether Schistosoma mansoni causes experimental PH associated with pulmonary vascular remodeling in an interleukin (IL)-13-dependent manner. IL-13Ralpha1 is the canonical IL-13 signaling receptor, whereas IL-13Ralpha2 is a competitive nonsignaling decoy receptor. Wild-type, IL-13Ralpha1(-/-), and IL-13Ralpha2(-/-) C57BL/6J mice were percutaneously infected with S. mansoni cercariae, followed by i.v. injection of eggs. We assessed PH with right ventricular catheterization, histological evaluation of pulmonary vascular remodeling, and detection of IL-13 and transforming growth factor-beta signaling. Infected mice developed pulmonary peri-egg granulomas and arterial remodeling involving predominantly the vascular media. In addition, gain-of-function IL-13Ralpha2(-/-) mice had exacerbated vascular remodeling and PH. Mice with loss of IL-13Ralpha1 function did not develop PH and had reduced pulmonary vascular remodeling. Moreover, the expression of resistin-like molecule-alpha, a target of IL-13 signaling, was increased in infected wild-type and IL-13Ralpha2(-/-) but not IL-13Ralpha1(-/-) mice. Phosphorylated Smad2/3, a target of transforming growth factor-beta signaling, was increased in both infected mice and humans with the disease. Our data indicate that experimental schistosomiasis causes PH and potentially relies on up-regulated IL-13 signaling.
Graham
Brian B
BB
Program in Translational Lung Research, Pulmonary and Critical Care Medicine, University of Colorado, Denver, Colorado, USA. brian.graham@ucdenver.edu
Mentink-Kane
Margaret M
MM
El-Haddad
Hazim
H
Purnell
Shawn
S
Zhang
Li
L
Zaiman
Ari
A
Redente
Elizabeth F
EF
Riches
David W H
DW
Hassoun
Paul M
PM
Bandeira
Angela
A
Champion
Hunter C
HC
Butrous
Ghazwan
G
Wynn
Thomas A
TA
Tuder
Rubin M
RM
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D006099:Granuloma / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D018793:Interleukin-13 / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D012550:Schistosoma mansoni / Q000276:immunology*; D012552:Schistosomiasis / Q000150:complications* / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000276:immunology; D051900:Smad3 Protein / Q000276:immunology; D015854:Up-Regulation / Q000502:physiology
D018793:Interleukin-13; D051899:Smad2 Protein; D051900:Smad3 Protein