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Aberrant transforming growth factor beta1-angiotensin II crosstalk in chronic obstructive pulmonary disease parenchymal fibroblasts Wee, Tracee

Abstract

Rationale: The airflow limitation in Chronic Obstructive Pulmonary Disease (COPD) is caused by small airways obstruction and/or obliteration and emphysematous destruction of parenchymal tissue. Our group previously characterized a gene expression signature for emphysema that included members of the TGFβ1 and Angiotensin (ANG) II signaling family. Further, we have shown that isolated parenchymal lung fibroblasts from severe COPD patients are unable to contract collagen 1α1 efficiently, but this impairment is reversed with the addition of TGFβ1 or the tripeptide Gly-His-Lys-Copper (GHK-Cu). Thus, we hypothesize that dysregulated ANG II-TGFβ1 crosstalk within the lung fibroblasts of COPD patients disrupts normal wound repair processes leading to disease. Methods: Parenchymal fibroblasts from ex-smokers with normal lung function (n=9), moderate COPD (GOLD II, n=5) and very severe COPD (GOLD IV, n=5) were treated with TGFβ1 (10 ng/mL), ANG II (100 nM) or GHK-Cu (100 nM) to evaluate the relationship between TGFβ1 and ANG II signaling and the potential of GHK-Cu as a therapeutic. Gene expression analysis using NanoString was performed on lung tissues from healthy (n=3) and COPD GOLD IV (n=3) donors. Comparisons were made using student’s t-test, paired t-tests or ANOVA. Results: TGFβ1 gene expression was reduced in COPD tissues (P

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