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Keratinocyte growth factor expression is suppressed in early acute lung injury/acute respiratory distress syndrome by smad and c-Abl pathways.

Abstract：

OBJECTIVE:Keratinocyte growth factor (KGF) is expressed primarily by fibroblasts, is important for alveolar epithelial proliferation/function, and protects against lung injury in multiple animal models. We wished to determine whether acute lung injury/acute respiratory distress syndrome (ALI/ARDS) alveolar fluid induces KGF and fibroblast genes important for alveolar repair. DESIGN:A single-center cohort study enrolling patients between 2004 and 2006. SETTING:A medical intensive care unit of a tertiary care medical center. PATIENTS:Adult patients meeting the American-European Consensus Conference definition of ALI/ARDS. INTERVENTIONS:Patients with ALI/ARDS were enrolled, and lavage fluid was collected within 48 hours of intubation. Lavage fluid was also collected from two control cohorts. The patients with ALI/ARDS were followed for 28 days or until death. MEASUREMENT AND MAIN RESULTS:Fifteen patients with ALI/ARDS, five patients with cardiogenic edema, and five normal lung parenchyma controls were enrolled from 2004 to 2006. Primary normal human lung fibroblasts were incubated with bronchoalveolar lavage fluid and assessed for KGF, connective tissue growth factor, alpha-smooth muscle actin, and collagen 1 expression by real-time reverse transcriptase-polymerase chain reaction. Fibroblasts incubated with ALI/ARDS lavage fluid expressed 50% less KGF messenger RNA than those incubated with lavage fluid from CE patients (p < 0.01) and 33% than normal parenchymal controls (p < 0.03). Lavage fluid from patients with ALI/ARDS induced more connective tissue growth factor (p < 0.05), collagen 1 (p < 0.03), and alpha-smooth muscle actin (p < 0.04) than from CE patients. Preincubation of normal human lung fibroblasts with the transforming growth factor (TGF)-beta1 receptor/smad phosphorylation inhibitor SB431542 increased ALI/ARDS-induced KGF expression by 40% (p < 0.04). In cultured human lung fibroblasts, TGF-beta1 suppressed KGF messenger RNA and protein expression, which were reversed by SB431542 and by the c-Abl inhibitor, imatinib mesylate, but not by the p38 map kinase inhibitor, SB203580. CONCLUSIONS:ALI/ARDS alveolar fluid suppresses KGF expression, in part, due to TGF-beta1. TGF-beta1 suppression of KGF requires both smad phosphorylation and c-Abl activation.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Chandel NS,Budinger GR,Mutlu GM,Varga J,Synenki L,Donnelly HK,Zirk A,Eisenbart J,Jovanovic B,Jain M

doi

10.1097/CCM.0b013e31819fc81a

subject

Has Abstract

pub_date

2009-05-01 00:00:00

pages

1678-84

issue

eissn

0090-3493

issn

1530-0293

journal_volume

pub_type

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Keratinocyte growth factor expression is suppressed in early acute lung injury/acute respiratory distress syndrome by smad and c-Abl pathways.