|
 
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| POSTGRADUATE FORUM |
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| Year : 2023 | Volume
: 3
| Issue : 2 | Page : 79-81 |
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Mechanotransduction in fibrosis
Ravindran Chetambath1, Nithya Ravindran2
1 Senior Consultant & Chief of Medical Services, Baby Memorial Hospital, Calicut, Kerala, India
2 Clinical Research Fellow, Department of Histopathology, NHS Trust, UK
| Date of Submission | 02-Jan-2023 |
| Date of Acceptance | 20-Jan-2023 |
| Date of Web Publication | 02-May-2023 |
Correspondence Address:
Dr. Ravindran Chetambath
Nvaneeth, PHED Road, Kozhikode - 673 020, Kerala
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jalh.jalh_1_23
Mechanotransduction is the phenomenon of conversion of mechanical forces to biochemical signals in fibrosis. Knowledge on how mechanotransduction influences the behavior of cells and tissues will help to identify novel therapeutic targets for mechanomodulatory approaches. Innovative therapies based on these advances will potentially transform fibrotic healing into tissue regeneration.
Keywords: Cytoskeleton, extracellular matrix, mechanotransduction
How to cite this article:
Chetambath R, Ravindran N. Mechanotransduction in fibrosis. J Adv Lung Health 2023;3:79-81 |
| Introduction | |  |
The typical response to injury anywhere in the body is scar formation, which provides early restoration of tissue integrity rather than functional regeneration. Scar development serves as a rapid “patch” response, providing a survival advantage as an evolutionarily conserved repair mechanism. All phases of wound healing are influenced by mechanical forces, and there is increasing evidence that mechanical influences regulate postinjury inflammation and fibrosis across multiple organ systems. The intensity of scar formation and fibrosis is different in all organs. Lung being an organ with heavy collagen network, fibrosis is a usual phenomenon after tissue injury. Although fibrosis in the setting of cutaneous injury is highly visible, there are a variety of organ systems that demonstrate pathologic fibrotic response to injury, including lung tissue in idiopathic pulmonary fibrosis (IPF) and the cardiovascular system following ischemic insult.
Acute wound healing typically occurs through a complex cascade of carefully orchestrated biochemical and cellular events in overlapping phases such as hemostasis, inflammation, proliferation, and remodeling with scar formation.
| Mechanism | | |
Mechanical stress causes an infiltration of inflammatory cells and decreased apoptosis of local cells involved in the healing response, resulting in proliferative scarring.[1] Mechanical force regulates fibrosis in part through an inflammatory focal adhesion kinase (FAK)-extracellular signal-regulated kinase-monocyte chemotactic protein-1 pathway.[2] The impact of FAK signaling on fibrosis formation has been demonstrated in lung tissue using a bleomycin-induced pulmonary fibrosis model in mice.[3],[4] Bleomycin, originally developed as an anticancer agent, causes an inflammatory response resembling acute lung injury and ultimately leads to the development of fibrosis, which can be markedly decreased by FAK inhibition. Through the process of mechanotransduction, cells are able to convert mechanical stimuli into biochemical or transcriptional changes.[5] This signal transduction involves proteins and molecules of the extracellular matrix (ECM), the cytoplasmic membrane, the cytoskeleton, and the nuclear membrane, eventually affecting the nuclear chromatin at a genetic and epigenetic level. Specifically, the response to continuous mechanical overload is a maladaptive remodeling of myocytes and the ECM, as well as increased interstitial fibrosis. There will be ECM activation through cellular traction forces and extracellular stretch. This is followed by cell surface transmembrane mechanotransduction. The next stage is mechanotransduction through cytoskeleton and nuclear mechanotransduction.
Mechanotransduction pathways are also important in the myocardium, as pathological hypertrophy can result from the abnormal cardiac workloads associated with systemic hypertension, aortic stenosis, or myocardial infarction.[6]
| Extracellular Matrix | | |
ECM is a dynamic and living component possessing multiple functions, including playing a pivotal role in cell adhesion, migration, differentiation, proliferation, apoptosis, and mechanotransduction. Reciprocal communication of mechanical cues between the ECM and cells can even directly influence gene expression, providing at least one mechanism of how physical cues from the ECM are able to alter cell functionality and phenotype. Mechanical forces can expose hidden domains and alter the spatial density of growth factors within the ECM, thereby influencing cell behavior. Finally, cytokines such as transforming growth factor-β (TGF-β) can bind to ECM domains and be released based on mechanical cues. Microenvironmental cues can influence fibroblast proliferation and collagen production through mechanoresponsive cell surface receptors. TGF-β superfamily has a significant influence on fibrosis and inflammation.
| Mediators | | |
Multiple interrelated signaling pathways have been shown to participate in the complex mechanism of intracellular mechanotransduction. Mediators responsible for transducing signals from the biomechanical environment include integrin–matrix interactions, growth factor receptors (for TGF-β), G-protein-coupled receptors, mechanoresponsive ion channels (e.g., Ca2+), and cytoskeletal strain responses. Upregulation of mechanotransduction signaling pathways in the healing grafts is identified through single-cell RNA sequencing, Applying a hydrogel containing FAK inhibitor to the grafts improved healing and reduced contracture and scar formation, with anti-inflammatory effects in the acute setting and proregenerative effects at a later phase.
| Therapeutic Targets | | |
The above findings suggest that FAK inhibition could be beneficial for the treatment of injuries. The major therapeutic strategies involving the TGF-β pathway thus include using neutralizing antibodies to TGF-βl and 2 or increasing TGF-β3. Neutralizing antibodies bind directly to the ligand and prevent receptor activation, and TGF-β1- and TGF-β2-specific antibodies have been successfully used to reduce fibrosis in a number of organs in animal models. The first clinical trial assessing an anti-TGF-β antibody (metelimumab) was used for patients with systemic sclerosis and demonstrated no significant improvement. A similar lack of benefit was seen in a Phase II clinical trial using imatinib mesylate, an inhibitor of TGF-β and platelet-derived growth factor (PDGF) signaling, for the treatment of scleroderma.[7]
Nintedanib, an antifibrotic agent used in IPF, is a potent small molecule inhibitor of the receptor tyrosine kinases such as PDGF, fibroblast growth factor, and vascular endothelial growth factor receptor. Nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM.[8]
Pirfenidone, another antifibrotic agent used in IPF, attenuates the production of TGF-β1. By suppressing TGF-β1, pirfenidone inhibits TGF-β1-induced differentiation of human lung fibroblasts into myofibroblasts, thereby preventing excess collagen synthesis and ECM production.[9]
| Conclusion | | |
A thorough understanding of the various signaling pathways involved in scar formation is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Many molecules are being tried to prevent fibrosis based on mechanotransduction such as anti-TGF-beta 1 and 2. More research is needed to identify different biochemical pathways, leading to fibrosis which may help in targeting these molecules to prevent fibrosis. Pirfenidone and nintedanib, presently used as antifibrotic agents in IPF, act by inhibiting various stages of fibroblast proliferation implicated in mechanotransduction.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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