CF airway smooth muscle transcriptome reveals a role for PYK2

Area of Science:

• Pulmonary Medicine
• Molecular Biology
• Pharmacology

Background:

• Abnormal airway smooth muscle function is implicated in cystic fibrosis (CF) airway disease.
• Newborn CF pigs exhibit intrinsic airway smooth muscle dysfunction, including increased basal tone and abnormal calcium handling, independent of infection or inflammation.

Purpose of the Study:

• To investigate the airway smooth muscle transcriptome changes due to CFTR loss.
• To identify novel therapeutic targets for CF airway smooth muscle dysfunction.

Main Methods:

• Total RNA sequencing of newborn wild-type and CF pig airway smooth muscle.
• Connectivity mapping to identify small molecules reversing CF-associated gene expression.
• Assessing PYK2 phosphorylation and the effect of its inhibition on smooth muscle contraction.
• In vivo testing of NVP-TAE684 in wild-type mice.

Main Results:

• RNA sequencing revealed significant alterations in muscle contraction-related genes, ontologies, and pathways in CF airway smooth muscle.
• NVP-TAE684, a PYK2 inhibitor, demonstrated a reversed transcriptional signature.
• Increased PYK2 phosphorylation was observed in CF airway smooth muscle, and its inhibition reduced contraction.
• In vivo NVP-TAE684 treatment decreased methacholine-induced airway smooth muscle contraction in mice.

Conclusions:

• CFTR loss induces distinct transcriptomic changes in airway smooth muscle, highlighting potential therapeutic avenues.
• PYK2 is a potential therapeutic target for CF airway smooth muscle dysfunction.
• Newborn CF pigs serve as a valuable model for understanding airway smooth muscle biology and developing therapeutics for CF and hyperreactive airway diseases.