Piezo channels modulate human lung fibroblast function.

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.