Abstract
Pulmonary fibrosis is the chronic-progressive replacement of healthy lung tissue by extracellular matrix, leading to the destruction of the alveolar architecture and ultimately death. Due to limited pathophysiological knowledge, causal therapies are still missing and consequently the prognosis is poor. Thus, there is an urgent clinical need for models to derive effective therapies. Polo-like kinase 2 (PLK2) is an emerging regulator of fibroblast function and fibrosis. We found a significant downregulation of PLK2 in four different entities of human pulmonary fibrosis. Therefore, we characterized the pulmonary phenotype of PLK2 knockout (KO) mice. Isolated pulmonary PLK2 KO fibroblasts displayed a pronounced myofibroblast phenotype reflected by increased expression of αSMA, reduced proliferation rates and enhanced ERK1/2 and SMAD2/3 phosphorylation. In PLK2 KO, the expression of the fibrotic cytokines osteopontin and IL18 was elevated compared to controls. Histological analysis of PLK2 KO lungs revealed early stage remodeling in terms of alveolar wall thickening, increased alveolar collagen deposition and myofibroblast foci. Our results prompt further investigation of PLK2 function in pulmonary fibrosis and suggest that the PLK2 KO model displays a genetic predisposition towards pulmonary fibrosis, which could be leveraged in future research on this topic.
Highlights
Introduction published maps and institutional affilPulmonary fibrosis encompasses multiple pathological conditions of the lungs in which functional alveolar tissue is progressively replaced by extracellular matrix [1,2]
Recent findings suggest that Polo-like kinase 2 (PLK2) is involved in non-pulmonary fibrosis regulation[13] and differential PLK2 expression has been demonstrated in pulmonary fibroblasts upon stimulation with TGFβ [14]
To ascertain whether PLK2 and its downstream targets are differentially regulated in pulmonary fibrosis, we analyzed gene expression in lung tissue samples from different fibrotic entities such as idiopathic pulmonary fibrosis (IPF), alveolar fibroelastosis (AFE), organizing pneumonia (OP) and systemic sclerosis (SSC)
Summary
Pulmonary fibrosis encompasses multiple pathological conditions of the lungs in which functional alveolar tissue is progressively replaced by extracellular matrix [1,2]. The nature of pulmonary fibrosis is highly heterogeneous with respect to disease-driving stimuli (e.g., smoking, radiation, dusts or drugs), pathological features and clinical outcome [1,2,3,4]. There are common motifs among the different entities of pulmonary fibrosis such as alveolar wall thickening due to collagen deposition, inflammation and fibroblast activation [1,2,5]. Animal models have been developed to investigate cellular and molecular pulmonary fibrosis mechanisms. Common animal models of pulmonary fibrosis include the application iations
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