Integrin [alpha]^sub 4^[beta]^sub 1^ regulates migration across basement membranes by lung fibroblasts: A role for phosphatase and tensin homologue deleted on chromosome 10

Idiopathic pulmonary fibrosis is a disease that is characterized by fibroblast accumulation and activation in the distal airspaces of the lung. We hypothesized that fibrotic lung fibroblasts migrate/invade across basement membranes by integrin-mediated mechanisms as a means of entering alveoli. We d...

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Bibliographic Details
Published inAmerican journal of respiratory and critical care medicine Vol. 168; no. 4; p. 436
Main Authors White, Eric S, Thannickal, Victor J, Carskadon, Shannon L, Dickie, Emily G
Format Journal Article
LanguageEnglish
Published New York American Thoracic Society 15.08.2003
Subjects
Chromosomes
Cloning
Collagen
Extracellular matrix
Fibroblasts
Flow cytometry
Genotype & phenotype
Membranes
Pathophysiology
Phosphatase
Pneumonia
Pulmonary fibrosis
Thoracic surgery
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Summary:Idiopathic pulmonary fibrosis is a disease that is characterized by fibroblast accumulation and activation in the distal airspaces of the lung. We hypothesized that fibrotic lung fibroblasts migrate/invade across basement membranes by integrin-mediated mechanisms as a means of entering alveoli. We demonstrate that in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis, fibronectin signaling is both necessary and sufficient for basement membrane migration/invasion across basement membranes. This effect is mediated through the alpha5beta1 integrin because blockade of fibronectin-alpha5 integrin ligation attenuated this response. In contrast, ligation of alpha4beta1 integrin inhibits basement membrane invasion by normal lung fibroblasts but not by fibrotic lung fibroblasts. This phenotypic difference is not related to surface expression of the alpha4beta1 integrin, as demonstrated by flow cytometry. In normal lung fibroblasts but not in fibrotic lung fibroblasts, we show that ligation of alpha4beta1 integrin induces a significant increase in phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activity. Fibrotic lung fibroblasts express constitutively less PTEN mRNA and protein as well as phosphatase activity in comparison to normal lung fibroblasts. Together, these data suggest that a loss of alpha4beta1 signaling via PTEN confers a migratory/invasive phenotype to fibrotic lung fibroblasts. Furthermore, this study implicates a loss of PTEN function in the pathophysiology of idiopathic pulmonary fibrosis.
ISSN:1073-449X
1535-4970