Homeodomain‐interacting protein kinase2 in human idiopathic pulmonary fibrosis

Abstract

Homeodomain-interacting protein kinase 2 (Hipk2) is an emerging player in cell response to genotoxic agents that contributes to the cell's decision between cell cycle arrest or apoptosis. HIPK2 acts as co-regulator of an increasing number of transcription factors and modulates many different basic cellular processes such as apoptosis, proliferation, DNA damage response, differentiation. Idiopathic pulmonary fibrosis (IPF) is characterized by an anatomical disarrangement of the lung due to fibroblast proliferation, extracellular matrix deposition and lung function impairment. Although the role of inflammation is still debated, attention has been focused on lung cell functions as fibroblast phenotype and activity. Aim of the present study was to analyze the loss of heterozygosity (LOH) at HIPK2 locus 7q32.34 in human lung fibroblasts and the HIPK2 expression in 15 IPF samples and in four primary fibroblast cell cultures isolated from IPF biopsies using semi-quantitative RT-PCR, Western blots and immunohistochemistry. We demonstrated a frequency of LOH in IPF fibroblasts of 46% for the internal D7S6440 microsatellite and 26.6% for the external D7S2468 microsatellite. Furthermore, we demonstrated low HIPK2 protein expression in those fibroblasts from IPF patients that present the HIPK2 LOH. The restoration of HIPK2 expression in IPF derived cells induced a significant reduction of chemoresistance after treatment with cisplatin. The results obtained allow us to hypothesize that HIPK2 dysfunction may play a role in fibroblasts behavior and in IPF pathogenesis. HIPK2 may be considered as a novel potential target for anti-fibrosis therapy.

Risk factors for primary Sjögren syndrome-associated interstitial lung disease

“…Small airway obstruction was detect in 76.1% (86/113) of the pSS patients. However, there were no significant differences in the MEF 25 , MEF 50 and MEF 75 values between the two groups.…”

“…Studies revealed mechanistic links between aging and lung fibrosis involving telomere attrition, genomic instability, and epigenetic alterations (24)(25)(26). Antihistone antibodies, a type of ANA, are correlated with severe pulmonary fibrosis in systemic sclerosis patients (27).…”

“…The DLCO adjusted for alveolar volume using the singlebreath method, with the values corrected for the present hemoglobin values. Small airway obstruction on pulmonary function tests represents that MEF 25 and MEF 50 were lower than 80% predicted, while PEF and MEF 75 were at normal range.…”

Mechanistic links between aging and lung fibrosis

“…There is emerging evidence that augmentation of DNA repair mechanisms may prolong lifespan and protect against aging-related disease (Baker et al 2013). Microsatellite instability and loss of heterozygosity (LOH) are more frequent in IPF (Vassilakis et al 2000; Ricci et al 2013). LOH at the homeodomain-interacting protein kinase 2 (HIPK2) gene, which is typically activated by genotoxic stimuli, was reported to underlie apoptosis resistance, specifically of IPF fibroblasts (Ricci et al 2013).…”

Genetic and Functional Analysis of Polymorphisms in the Human Dopamine Receptor and Transporter Genes in Small Cell Lung Cancer

“…Further details are reported in a previous study (Ricci et al, 2013). For detection, an ECL chemiluminescence system (Therma Scientific) was used.…”