Abstract
Mechano-transcription is a process whereby mechanical stress alters gene expression. The gastrointestinal (GI) tract is composed of a series of hollow organs, often encountered by transient or persistent mechanical stress. Recent studies have revealed that persistent mechanical stress is present in obstructive, functional, and inflammatory disorders and alters gene transcription in these conditions. Mechano-transcription of inflammatory molecules, pain mediators, pro-fibrotic and growth factors has been shown to play a key role in the development of motility dysfunction, visceral hypersensitivity, inflammation, and fibrosis in the gut. In particular, mechanical stress-induced cyclooxygenase-2 (COX-2) and certain pro-inflammatory mediators in gut smooth muscle cells are responsible for motility dysfunction and inflammatory process. Mechano-transcription of pain mediators such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) may lead to visceral hypersensitivity. Emerging evidence suggests that mechanical stress in the gut also leads to up-regulation of certain proliferative and pro-fibrotic mediators such as connective tissue growth factor (CTGF) and osteopontin (OPN), which may contribute to fibrostenotic Crohn’s disease. In this review, we will discuss the pathophysiological significance of mechanical stress-induced expression of pro-inflammatory molecules, pain mediators, pro-fibrotic and growth factors in obstructive, inflammatory, and functional bowel disorders. We will also evaluate potential therapeutic targets of mechano-transcription process for the management of these disorders.
Highlights
The gastrointestinal (GI) tract is subject to mechanical stimuli constantly (Shi, 2017; Sarna and Shi, 2006)
Numerous in vitro and in vivo studies have demonstrated that mechanical stress profoundly alters gene expression in the GI tract especially smooth muscle cells
Mechano-transcription of pro-inflammatory molecules, pain mediators, fibrogenic and growth factors plays a critical role in motility dysfunction, abdominal pain, inflammation, fibrosis, and hyperplasia in various gastrointestinal disorders (Figure 5)
Summary
The gastrointestinal (GI) tract is subject to mechanical stimuli constantly (Shi, 2017; Sarna and Shi, 2006). These mechano-sensors transduce mechanical signals to intracellular signaling pathways involving PKC (i.e., PKCδ), PKD (PKD1), and MAPKs (p38, ERKs, and JNKs), leading to mechano-transcription of COX-2 in colonic SMC. Echistatin treatment has significantly inhibited stretch-induced activation of p38, but not ERKs and JNKs. The downstream pathway of integrin signaling was found to be important in mechano-transcription of COX-2 in gut SMC, as knockdown of integrin-linked kinase and focal adhesion kinase with specific siRNAs significantly suppressed mechanotranscription of COX-2 in the cells (Li et al, 2012a). Studies suggest that PKC-δ is linked to MAPKs ERKs, p38, and JNKs, whereas PKD is connected to MAPK p38 (Li et al, 2012a; Li et al, 2012b; Shi, 2017) (Figure 3B)
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