Background Pirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-β1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-β1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated. Methods The effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-β1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro. Results Compared to control lung fibroblasts, pirfenidone significantly restored TGF-β1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-β1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of α-smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1. Conclusions Overall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis. Electronic supplementary material The online version of this article (10.1186/s12931-019-1093-z) contains supplementary material, which is available to authorized users.
Circulating tumor cells (CTCs) have a crucial role in the clinical outcome of cancer patients. Detection of non-small cell lung cancer (NSCLC) using an antibody against epithelial cell adhesion molecule (EpCAM) in captured CTCs has low sensitivity; the loss of epithelial markers leads to underestimation of CTCs with mesenchymal phenotype. We propose a new approach for detection of viable CTCs, including those with epithelial-mesenchymal transition status (EMT-CTCs), using the new telomerase-specific replication-selective adenovirus (OBP-1101), TelomeScan F35. Peripheral venous blood samples and clinicopathological data were collected from 123 NSCLC patients. The sensitivity of CTC detection was 69.1%, and for patients with stage I, II, III and IV, it was 59.6%, 40.0%, 85.7%, and 75.0%, respectively. Among the EMT-CTC samples, 46% were vimentin positive and 39.0% of non-EMT-CTC samples were EpCAM positive. Patients testing positive for EMT-CTCs at baseline had poor response to chemotherapy (P = 0.025) and decreased progression-free survival (EMT-CTC positive vs. negative: 193 ± 47 days vs. 388 ± 47. days, P = 0.040) in comparison to those testing negative. TelomeScan F35 is a highly sensitive CTC detection system and will be a useful screening tool for early diagnosis of NSCLC patients. Mesenchymal-phenotype CTCs are crucial indicators of chemotherapeutic efficacy in NSCLC patients.
BackgroundRenal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury and a frequent occurrence in critically ill patients. Renal IRI releases proinflammatory cytokines within the kidney that induce crosstalk between the kidney and other organ systems. Atrial natriuretic peptide (ANP) has anti-inflammatory as well as natriuretic effects and serves important functions as a regulator of blood pressure, fluid homeostasis, and inflammation. The objective of the present study was to elucidate whether ANP post-treatment attenuates kidney-lung-heart crosstalk in a rat model of renal IRI.MethodsIn experiment I, a rat model of unilateral renal IRI with mechanical ventilation was prepared by clamping the left renal pedicle for 30 min. Five minutes after clamping, saline or ANP (0.2 μg/kg/min) was infused. The hemodynamics, arterial blood gases, and plasma concentrations of lactate and potassium were measured at baseline and at 1, 2, and 3 h after declamping. The mRNA expression and localization of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the kidney, lung, and heart were examined. In experiment II, a rat model of bilateral renal IRI without mechanical ventilation was prepared by clamping bilateral renal pedicles for 30 min. Thirty minutes after clamping, lactated Ringer's (LR) solution or ANP (0.2 μg/kg/min) was infused. Plasma concentrations of TNF-α, IL-6, and IL-1β were determined at baseline and at 3 h after declamping.ResultsIn unilateral IRI rats with mechanical ventilation, ANP inhibited the following changes induced by IRI: metabolic acidosis; pulmonary edema; increases in lactate, creatinine, and potassium; and increases in the mRNA expression of TNF-α, IL-1β, and IL-6 in the kidney and lung and IL-1β and IL-6 in the heart. It also attenuated the histological localization of TNF-α, IL-6, and nuclear factor (NF)-κB in the kidney and lung. In bilateral IRI rats without mechanical ventilation, ANP attenuated the IRI-induced increases of the plasma concentrations of potassium, IL-1β, and IL-6.ConclusionsRenal IRI induced injury in remote organs including the lung and the contralateral kidney. ANP post-treatment ameliorated injuries in these organs by direct tissue protective effect and anti-inflammatory effects, which potentially inhibited inter-organ crosstalk.
Cancer-associated fibroblasts (CAFs) regulate cancer progression through the modulation of extracellular matrix (ECM) and cancer cell adhesion. While undergoing a series of phenotypic changes, CAFs control cancer-stroma interactions through integrin receptor signaling. Here, we isolated CAFs from patients with non-small cell lung cancer (NSCLC), and examined their gene expression profiles. We identified collagen type XI α1 (COL11A1), integrin α11 (ITGA11), and the ITGA11 major ligand collagen type I α1 (COL1A1) among the 390 genes that were significantly enriched in NSCLC-associated CAFs. Increased ITGA11 expression in cancer stroma was correlated with a poor clinical outcome in patients with NSCLC. Increased expression of fibronectin and collagen type I induced ITGA11 expression in CAFs. The cellular migration of CAFs toward collagen type I and fibronectin was promoted via ERK1/2 signaling, independently of the fibronectin receptor integrin α5β1. Additionally, ERK1/2 signaling induced ITGA11 and COL11A1 expression in cancer stroma. We, therefore, propose that targeting ITGA11 and COL11A1 expressing CAFs to block cancer-stroma interactions may serve as a novel, promising anti-tumor strategy.
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