Toll-like receptor 4-deficient mice are resistant to chronic hypoxia-induced pulmonary hypertension.
Current data suggest that Toll-like receptor 4 (TLR4), a key molecule in the innate immune response, may also be activated following tissue injury. Activation of this receptor is known to induce the production of several proinflammatory cytokines. Given that pulmonary inflammation has been shown to be a key contributor to chronic hypoxia-induced pulmonary vascular remodeling, the authors hypothesized that TLR4-deficient mice would be less susceptible to pulmonary hypertension (PH) as compared to mice with intact TLR4. TLR4-deficient and TLR4-intact strains of inbred mice were exposed to 4, 8, and 16 weeks of hypoxia (0.10 FiO(2)) or normoxia (0.21 FiO(2)) in a normobaric chamber. After chronic hypoxic exposure, TLR4-intact mice developed significant PH evidenced by increased right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery medial thickening. In contrast, TLR4-deficient mice had no significant change in any of these parameters and this was associated with decreased pulmonary vascular inflammatory response as compared to the TLR4-intact mice. These results suggest that TLR4 deficiency may decrease the susceptibility to developing PH by attenuating the pulmonary vascular inflammatory response to chronic hypoxia.
Young
Karen C
KC
Department of Pediatrics/Division of Neonatology and Batchelor Children's Research Institute, University of Miami, Miller School of Medicine, Miami, FL 33101, USA. kyoung3@med.miami.ed
Hussein
Sameh M A
SM
Dadiz
Rita
R
deMello
Daphne
D
Devia
Carlos
C
Hehre
Dorothy
D
Suguihara
Cleide
C
D000818:Animals; D001794:Blood Pressure; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular; D000860:Hypoxia / Q000150:complications* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000503:physiopathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse