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Pechkovsky DV, Hackett TL, An SS, Shaheen F, Murray LA, Knight DA: Human Lung Parenchyma but not Proximal Bronchi Produces Fibroblasts with Enhanced TGF{beta} Signaling and {alpha}SMA Expression. Am J Respir Cell Mol Biol. 2010 Jan 8.
Given the contribution various fibroblast subsets make to wound healing and tissue remodeling, the concept of lung fibroblast heterogeneity is of great scientific interest. However, the mechanisms contributing to this heterogeneity are unknown. To this aim, we compared molecular and biophysical characteristics of fibroblasts concurrently isolated from normal human proximal bronchi (B-FBR) and distal lung parenchyma (P-FBR). Using quantitative RT-PCR, spontaneous expression of more than 30 genes related to repair and remodeling was analyzed. All P-FBR lines demonstrated significantly increased basal alphaSMA mRNA and protein expression levels when compared with donor-matched B-FBR. These differences were not associated with gender, age or disease history of lung tissue donors. In contrast to B-FBR, P-FBR displayed enhanced TGFbeta/Smad signaling at baseline, and inhibition of either ALK-5 or neutralization of endogenously produced and activated TGFbeta substantially decreased basal alphaSMA protein in P-FBR. Both B-FBR and P-FBR up-regulated alphaSMA after stimulation with TGFbeta1, and basal expression levels of TGFbeta1, TGFbetaRI and TGFbetaRII were not significantly different between fibroblast pairs. Blockade of metalloproteinase-dependent activation of endogenous TGFbeta did not significantly modify alphaSMA expression in P-FBR. However, resistance to mechanical tension of these cells was significantly higher in comparison with B-FBR, and added TGFbeta1 significantly increased stiffness of both cell monolayers. Our data suggest that in contrast with human normal bronchial tissue explants, lung parenchyma produces mesenchymal cells with a myofibroblastic phenotype by intrinsic mechanisms of TGFbeta activation in feed-forward manner. These results also offer a new insight into mechanisms of human fibroblast heterogeneity and their function in the airway and lung tissue repair and remodeling. |
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