Phosphoinositide 3-Kinase Mediates Calcium Sensitization in Human Airway Smooth Muscle

University Of Pennsylvania, Philadelphia PA

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Abstract

Airway hyper-responsiveness (AHR) and inflammation, hallmarks of asthma, manifest upon exposure to environmental insults such as allergens and toxicants. The mainstay of treatment includes anti-inflammatory agents and bronchodilators, which reverse shortening of human airway smooth muscle (HASM). However, about half of patients with asthma have inadequate control with current therapies and require novel drugs. Our data suggests that HASM shortening is dependent upon phosphatidylinositol 3-kinase (PI3K), a kinase involved in a variety of cellular functions. We also show that inhibition of PI3K results in the bronchodilation of human airways. However, the role of PI3K in smooth muscle contraction and relaxation remains unknown. Since the PI3K/RhoA/Rho Kinase (ROCK) axis modulates agonist-mediated HASM shortening, I hypothesize that PI3K activation increases calcium sensitivity, thereby amplifying shortening and driving AHR in asthma. Using techniques such as hPCLS contraction assays, ROCK activation assays, stable isotope labeling by amino acids in cell culture (SILAC) based quantitative phosphoproteomics, and quantitative analysis of single HASM cell force generation, I will determine the role of PI3K in modulating airway smooth muscle shortening. I aim to (1) Investigate whether PI3K modulates agonist-induced airway bronchoconstriction by increasing sensitivity to calcium in HASM; and (2) Determine whether asthma modulates calcium sensitization pathways in HASM. Completion of these aims will provide a deeper understanding of mechanisms driving AHR in asthma. Ideally, understanding the molecular pathways modulating calcium sensitization in HASM will identify novel therapeutics for bronchodilator therapy.