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Activation of Heat Shock Response Augments Fibroblast Growth Factor-1 Expression in Wounded Lung Epithelium: A Possible Mechanism for Progressive Lung Fibrosis

ABSTRACT: Human cells were resistant to apoptosis induced by TNFα and Heat Shock (HS). Wound healing in NHBE and A549 cells occurred 30-50% more rapidly when cells were exposed to HS immediately after wounding. Gene expression analysis showed that HS synergized with wounding to increase expression of FGF1 by 30-fold. Enhanced FGF1 expression was blocked by inhibitors of p38 MAP kinase (SB203580) and heat shock factor (HSF)-1 (KNK-437) and in HSF1 knockout BEAS2B cells. Accelerated wound closure was reduced by SB203580, KNK-437, and by SU-5402, an inhibitor of FGF receptors 1 and 3. FGF1 was expressed in A549 and BEAS2B from promoters C and D. Finally, we found that FGF1 and HSP70 mRNA levels were 7.5- and 5.9-fold higher in IPF than normal lung. Confocal immunofluorescent microscopy showed FGF1 and HSP70 to be co-localized in affected regions of IPF but not normal lung. Epithelial injury and HS synergize to activate expression of FGF1 in lung epithelium through mechanisms that include p38 MAP kinase and HSF1. FGF1 expression and heat shock pathway activation is increased and colocalizes to defined foci in IPF lung, suggesting this pathway may have an important impact on lung injury, healing, and fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83844 | GEO | 2017/09/08

SECONDARY ACCESSION(S): PRJNA327182

REPOSITORIES: GEO

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Project description:The etiology of trauma-hemorrhage shock-induced acute lung injury has been difficult to elucidate due, at least in part, to the inability of in vivo studies to separate the non-injurious pulmonary effects of trauma-hemorrhage from the tissue injurious ones. To circumvent this in vivo limitation, we utilized a model of trauma-hemorrhagic shock (T/HS) in which T/HS-lung injury was abrogated by dividing the mesenteric lymph duct. In this way, it was possible to separate the pulmonary injurious response from the non-injurious systemic response to T/HS by comparing the pulmonary molecular response of rats subjected to T/HS which did and did not develop lung injury as well as to non-shocked rats. Utilizing high-density oligonucleotide arrays and treatment group comparisons of whole lung tissue collected at 3 hours after the end of the shock or sham-shock period, 139 of the 8,799 assessed genes were differentially expressed. Experiment Overall Design: Four groups of rats (n=3) were studied in order to identify changes in pulmonary gene expression associated with T/HS, both in the presence and absence of lung injury. These included trauma-sham shock (T/SS) rats which had a laparotomy (trauma) but were not subjected to hemorrhagic shock. These rats had no lung injury and served as controls for rats which were subjected to T/HS (laparotomy plus 90 min of shock) and had lung injury. Differences in gene expression between these two groups would represent both the effects of hemorrhagic shock as well as lung injury. To distinguish the gene response of hemorrhagic shock from the gene response associated with lung injury, gene expression was also compared between T/HS rats (hemorrhage and lung injury) and rats subjected to T/HS plus lymph duct ligation (T/HS-LDL), since the T/HS-LDL rats experienced hemorrhagic shock but had no measurable lung injury. Lastly, to identify hemorrhagic shock- modified genes, the pulmonary gene response of T/HS-LDL (hemorrhage without lung injury) were compared to rats subjected to T/SS plus LDL (no hemorrhage or lung injury). Three hours after the end of the 90 min shock or sham-shock period (i.e. 4.5 hrs after the induction of T/HS), the rats were sacrificed and specimens harvested for genechip analysis and histology.

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Activation of Heat Shock Response Augments Fibroblast Growth Factor-1 Expression in Wounded Lung Epithelium: A Possible Mechanism for Progressive Lung Fibrosis

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