# Hic-5 transduces mechanical force that drives a vicious cycle of bronchoconstriction

## TL;DR

The protein Hic-5 helps convert mechanical force into biological signals that worsen bronchoconstriction, suggesting a new target for treating asthma.

## Contribution

Hic-5 is identified as a novel mechanosensor in airway epithelial cells that drives disease progression during bronchoconstriction.

## Key findings

- Hic-5 expression increases in airway basal cells under mechanical compression.
- Hic-5 knockdown reduces stress fiber formation and alters 70% of mechanically regulated transcripts.
- Hic-5 deficiency decreases secretion of ET-1, a bronchoconstrictor, breaking the cycle of airway constriction.

## Abstract

Mechanical forces are essential for the function of key organs, including the bladder, bowel, heart, and lung<1/sup>. These organs often encounter excessive or dysregulated mechanical forces, which are associated with pathological conditions. However, the key regulators of mechanotransduction remain poorly understood. As an example of how excessive mechanical force imposed on airway epithelia could lead to mechanotransduction<2/sup> that alters the transcriptome<3/sup> and secretome<4/sup> and induces cell death<5/sup>, all of which contribute to disease progression<6,7/sup>, we used human airway epithelial cells in air-liquid interface culture to mimic bronchoconstriction. We show that Hic-5, a focal adhesion adaptor protein, functions as a key regulator of mechanoresponses in the airway. Hic-5 expression is significantly induced in airway basal cells following mechanical compression or bronchoconstriction. Hic-5 knockdown using antisense oligonucleotides protects against stress fiber formation and abolishes approximately 70% of transcripts differentially regulated by mechanical compression. Moreover, Hic-5 deficiency attenuates secretion of ET-1, a potent bronchoconstrictor. Our data show that during an asthma exacerbation, Hic-5 reinforces a vicious cycle of bronchoconstriction through the secretion of ET-1. We establish Hic-5 as a critical link between mechanical stress and epithelial activation in human disease, implicating dysregulated mechanical forces as active drivers of disease progression with therapeutic relevance.