Magnitude-dependent regulation of pulmonary endothelial cell barrier function by cyclic stretch.
Ventilator-induced lung injury syndromes are characterized by profound increases in vascular leakiness and activation of inflammatory processes. To explore whether excessive cyclic stretch (CS) directly causes vascular barrier disruption or enhances endothelial cell sensitivity to edemagenic agents, human pulmonary artery endothelial cells (HPAEC) were exposed to physiologically (5% elongation) or pathologically (18% elongation) relevant levels of strain. CS produced rapid (10 min) increases in myosin light chain (MLC) phosphorylation, activation of p38 and extracellular signal-related kinase 1/2 MAP kinases, and actomyosin remodeling. Acute (15 min) and chronic (48 h) CS markedly enhanced thrombin-induced MLC phosphorylation (2.1-fold and 3.2-fold for 15-min CS at 5 and 18% elongation and 2.1-fold and 3.1-fold for 48-h CS at 5 and 18% elongation, respectively). HPAEC preconditioned at 18% CS, but not at 5% CS, exhibited significantly enhanced thrombin-induced reduction in transendothelial electrical resistance but did not affect barrier protective effect of sphingosine-1-phosphate (0.5 microM). Finally, expression profiling analysis revealed a number of genes, including small GTPase rho, apoptosis mediator ZIP kinase, and proteinase activated receptor-2, to be regulated by CS in an amplitude-dependent manner. Thus our study demonstrates a critical role for the magnitude of CS in regulation of agonist-mediated pulmonary endothelial cell permeability and strongly suggests phenotypic regulation of HPAEC barrier properties by CS.
Birukov
Konstantin G
KG
Division of Pulmonary and Critical Care Medicine, Johns Hopkins Univ. School of Medicine, 5501 Hopkins Bayview Circle, JHAAC, 5A.42, Baltimore, MD 21224, USA. kbirukov@jhmi.edu
Jacobson
Jeffrey R
JR
Flores
Alejandro A
AA
Ye
Shui Q
SQ
Birukova
Anna A
AA
Verin
Alexander D
AD
Garcia
Joe G N
JG
D002199:Capillary Permeability / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017629:Gap Junctions / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D018994:Myosin Light Chains / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010507:Periodicity; D010766:Phosphorylation / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013314:Stress, Mechanical; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors
D018994:Myosin Light Chains; D013917:Thrombin