Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge

Abstract

CTGF is upregulated in patients with idiopathic pulmonary fibrosis (IPF), characterized by the deposition of a pathological extracellular matrix (ECM). Additionally, many omics studies confirmed that aberrant cellular senescence-associated mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, alveolar endothelial cells, fibroblasts, and macrophages). Here, we reviewed the role of the CTGF in IPF lung cells to mediate anomalous senescence-related metabolic mechanisms that support the fibrotic environment in IPF.

Keywords: CTGF; chronic respiratory diseases; idiopathic pulmonary fibrosis; metabolic dysregulation; mitochondria dysfunction; pro-fibrotic; senescence.

Figure 1

(A) Regulation of CTGF. CTGF expression is mainly regulated at the transcriptional level by various stimuli factors either directly or through cross-talk with cell surface receptors (TGF-β) that induce signaling pathways that recruit transcription factors (YAP/TAZ/TEAD, SMAD2, Ets-1, PI3K-AKT, and Fox0) to the nucleus, inhibiting or stimulating the expression of CTGF; (B) CTGF regulates aberrant metabolic responses associated with senescence of alveolar epithelial cells, endothelial cells, fibroblasts, and alveolar macrophages. As an essential downstream mediator of TGF-β1-induced mitophagy, CTGF induces mtROS and increases glycolysis, lactate, and glutaminolysis, leading to apoptosis resistance in macrophages and fibroblasts. Conversely, accumulation of mtROS inhibits mitophagy to promote alveolar epithelial apoptosis; (C) CTGF maintains pro-fibrotic environment. Injured AECII secretes CTGF via autocrine and paracrine, inducing alveolar epithelial cells undergoing EMT to promote fibroblasts’ migration and proliferation, regulating myofibroblast differentiation, and driving macrophage polarization, resulting in ECM deposition and lung fibrosis.

Figure 2

CTGF-regulated metabolic dysregulation and mitochondria dysfunction contribute to cellular senescence. CTGF drives metabolic- and mitochondria-dysfunction-associated mitophagy and contributes to cellular senescence. Briefly, CTGF expression in IPF cells leads to ROS production, metabolism disturbance, and paradoxical apoptosis, leading to mitophagy induction. Autophagy drives the onset of senescence. Senescent IPF lung epithelial cells, fibroblasts, and myofibroblasts secrete CTGF as pro-inflammatory SASP to induce senescence-associated fibrotic effects in surrounding cells via paracrine and autocrine signaling. Oxidative stress, autophagy, and senescence may also contribute to CTGF-induced fibrosis and ECM remodeling.