Tropomyosin 2.1 collaborates with fibronectin to promote TGF-β1-induced contraction of human lung fibroblasts

Abstract

Many lung diseases are characterized by fibrosis, leading to impaired tissue patency and reduced lung function. Development of fibrotic tissue depends on two-way interaction between the cells and the extra-cellular matrix (ECM). Concentration-dependent increased stiffening of the ECM is sensed by the cells, which in turn increases intracellular contraction and pulling on the matrix causing matrix reorganization and further stiffening. It is generally accepted that the inflammatory cytokine growth factor β1 (TGF-β1) is a major driver of lung fibrosis through the stimulation of ECM production. However, TGF-β1 also regulates the expression of members of the tropomyosin (Tm) family of actin associating proteins that mediate ECM reorganization through intracellular-generated forces. Thus, TGF-β1 may mediate the bi-directional signaling between cells and the ECM that promotes tissue fibrosis. Using combinations of cytokine stimulation, mRNA, protein profiling and cellular contractility assays with human lung fibroblasts, we show that concomitant induction of key Tm isoforms and ECM by TGF-β1, significantly accelerates fibrotic phenotypes. Knocking down Tpm2.1 reduces fibroblast-mediated collagen gel contraction. Collectively, the data suggest combined ECM secretion and actin cytoskeleton contractility primes the tissue for enhanced fibrosis. Our study suggests that Tms are at the nexus of inflammation and tissue stiffening. Small molecules targeting specific Tm isoforms have recently been designed; thus targeting Tpm2.1 may represent a novel therapeutic target in lung fibrosis.

Bronchoalveolar-Lavage-Derived Fibroblast Cell Line (B-LSDM7) as a New Protocol for Investigating the Mechanisms of Idiopathic Pulmonary Fibrosis

“…However, since CD105 positivity is shared with mesenchymal stromal/stem cells [25], we also considered simultaneous expression of collagen type-1 and fibronectin. TGF-β1 increases fibronectin and col1 expression in HLF [26]. The same expression of collagen type 1 and fibronectin was reported in both cell lines.…”

Exhaled biomarkers in adults with non-productive cough

“…Fibrinogen has previously been described to be increased in blood samples among patients with asthma and cough, compared to patients with asthma but without cough [32]. Also, the extracellular matrix protein fibronectin was increased among those with non-productive cough, a protein that also has been implicated in the pathogenesis of lung fibrosis [34,35]. Some proteins identified deserve specific attention with regard to the cough hypersensitivity theory.…”

Exhaled biomarkers in adults with non-productive cough

“…Fibrinogen has previously been described to be increased in blood samples among patients with asthma and cough, compared to patients with asthma but without cough [ 32 ]. Also, the extracellular matrix protein fibronectin was increased among those with non-productive cough, a protein that also has been implicated in the pathogenesis of lung fibrosis [ 34 , 35 ].…”