Abstract
BackgroundDuring wound healing processes fibroblasts account for wound closure by adopting a contractile phenotype. One disease manifestation of COPD is emphysema which is characterized by destruction of alveolar walls and our hypothesis is that fibroblasts in the COPD lungs differentiate into a more contractile phenotype as a response to the deteriorating environment.MethodsBronchial (central) and parenchymal (distal) fibroblasts were isolated from lung explants from COPD patients (n = 9) (GOLD stage IV) and from biopsies from control subjects and from donor lungs (n = 12). Tissue-derived fibroblasts were assessed for expression of proteins involved in fibroblast contraction by western blotting whereas contraction capacity was measured in three-dimensional collagen gels.ResultsThe basal expression of rho-associated coiled-coil protein kinase 1 (ROCK1) was increased in both centrally and distally derived fibroblasts from COPD patients compared to fibroblasts from control subjects (p < 0.001) and (p < 0.01), respectively. Distally derived fibroblasts from COPD patients had increased contractile capacity compared to control fibroblasts (p < 0.01). The contraction was dependent on ROCK1 activity as the ROCK inhibitor Y27632 dose-dependently blocked contraction in fibroblasts from COPD patients. ROCK1-positive fibroblasts were also identified by immunohistochemistry in the alveolar parenchyma in lung tissue sections from COPD patients.ConclusionsDistally derived fibroblasts from COPD patients have an enhanced contractile phenotype that is dependent on ROCK1 activity. This feature may be of importance for the elastic dynamics of small airways and the parenchyma in late stages of COPD.
Highlights
During wound healing processes fibroblasts account for wound closure by adopting a contractile phenotype
Derived fibroblasts from Chronic obstructive pulmonary disease (COPD) patients had a phalloidin staining pattern with parallel fibers attached to their lamellipodia typical for contractile cells. This was contrasted with the staining pattern in distally derived fibroblasts from control subjects and centrally derived fibroblasts from COPD patients and control subjects
Expression of proteins involved in fibroblast contraction We examined the expression of proteins known to be involved in fibroblast contraction: rho-associated coiled-coil protein kinase 1 (ROCK1), α-smooth muscle actin (α-SMA) and Rho A to elucidate the molecular mechanism for the increased contractility (Figure 3 A-C)
Summary
During wound healing processes fibroblasts account for wound closure by adopting a contractile phenotype. One disease manifestation of COPD is emphysema which is characterized by destruction of alveolar walls and our hypothesis is that fibroblasts in the COPD lungs differentiate into a more contractile phenotype as a response to the deteriorating environment. Fibroblasts are key players in wound healing as they are the main producer of extracellular matrix (ECM) and may adopt a contractile phenotype to promote wound closure [7,8]. It has been suggested that there exist different subsets of fibroblasts in central airways and in alveolar parenchyma, characterized by differences in morphology, production of ECM proteins and in the expression of α-SMA [15,16]. The fibroblast phenotypes were altered in fibroblasts isolated from severe COPD patients
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