AbstractsMedical & Health Science

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

by Tracee Wee

Institution: University of British Columbia
Department: Experimental Medicine
Degree: MS- MSc
Year: 2014
Record ID: 2045430
Full text PDF: http://hdl.handle.net/2429/46418


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<0.05), and exogenous TGFβ1 downregulated angiotensin receptor type 1 (AT1R) expression in fibroblasts from healthy control (P<0.05) but not COPD. This discrepant response was not due to inactive TGFβ1 signaling or changes in AT1R mRNA expression, and GHK-Cu was unable to correct this signaling defect. Expression of AT1R was significantly lower in COPD GOLD IV tissues (P<0.0001), and exogenous ANG II increased TGFβ1 production of parenchymal fibroblasts derived from all donor groups albeit levels were lower from COPD derived fibroblasts. Collagen 1α1 mRNA was increased in COPD lung tissue (P<0.0001), and the production of collagen 1α1 in response to exogenous TGFβ1 was increased in COPD derived fibroblasts (P<0.05). Conclusion: TGFβ1-ANG II crosstalk is defective in COPD parenchymal fibroblasts which could contribute to the development of emphysema through loss of cell responsiveness to TGFβ1, an important mediator in tissue repair.