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Piezo channels modulate human lung fibroblast function
Mengning Zheng1,2, Yang Yao2,3, Niyati A Borkar2
1Department of Respiratory and Critical Care Medicine, Guizhou Province People's Hospital, Guiyang, China.
Summary
Mechanical stretch in human lung fibroblasts increases extracellular matrix production via Piezo 1 (PZ1) channels. Targeting these mechanosensitive channels may reduce airway remodeling and fibrosis.
Area of Science:
- Cell biology
- Mechanobiology
- Pulmonary medicine
Background:
- Bronchial airways and lung parenchyma experience mechanical stretch during breathing and in conditions like mechanical ventilation, asthma, and COPD.
- This stretch can lead to airway remodeling characterized by increased extracellular matrix (ECM) production, a process critically involving fibroblasts.
- The precise mechanisms linking mechanical stretch to fibroblast-driven ECM remodeling, particularly the role of mechanosensitive channels, remain underexplored.
Purpose of the Study:
- To investigate the role of Piezo (PZ) channels, specifically Piezo 1 (PZ1), in mechanical stretch-induced airway remodeling in human lung fibroblasts.
- To elucidate the signaling pathways, including ERK and calcium influx, involved in PZ1-mediated responses to mechanical stretch.
- To assess the potential of targeting PZ channels as a therapeutic strategy for mitigating airway remodeling.
Main Methods:
- Human lung fibroblasts were subjected to a combination of static (10%) and dynamic (5%) stretch for 48 hours.
- Expression levels of Collagen I, fibronectin, alpha-smooth muscle actin (α-SMA), and PZ1 were measured.
- Experiments involved the use of a PZ1 agonist (Yoda1) and inhibitor (GsMTx4), as well as PZ1 knockdown via siRNA.
- ERK and Smad pathway activation was assessed, along with intracellular calcium ([Ca2+]i) responses to histamine.
Main Results:
- Mechanical stretch significantly increased the expression of Collagen I, fibronectin, and α-SMA.
- The PZ1 agonist Yoda1 mimicked and enhanced the stretch-induced increase in ECM components.
- Pretreatment with the PZ1 inhibitor GsMTx4 or PZ1 knockdown attenuated these stretch-induced effects.
- Stretch activated the ERK pathway, but not Smad, an effect dependent on PZ1.
- PZ1 knockdown blunted the enhanced [Ca2+]i responses to histamine observed after mechanical stretch.
Conclusions:
- Piezo 1 channels are essential mediators of mechanical stretch-induced extracellular matrix production in lung fibroblasts.
- PZ1 signaling involves ERK pathway activation and calcium influx, contributing to fibroblast activation and potential airway remodeling.
- Targeting Piezo channels in fibroblasts presents a promising therapeutic avenue for reducing ECM deposition and ameliorating lung fibrosis.
