Airway Smooth Muscle

Intracellular calcium plays a major role in airway smooth muscle (ASM) contraction and relaxation. Altered airway reactivity to bronchoconstrictors versus bronchodilators underlies diseases such as asthma and the septic lung. Drugs used in clinical practice (e.g., anesthesia, critical care) often affect intracellular calcium (Ca2+) concentration of ASM. Others may influence the sensitivity of smooth muscle for force generation. The laboratory is currently focused on four aspects of Ca2+ and force regulation (and dysregulation) in ASM:

1. Caveolar Regulation of Airway Hyperreactivity. Caveolin proteins form plasma membrane invaginations (caveolae) that may serve as scaffolding structures for integration of different signaling mechanisms. We are currently dissecting out the role of caveolin-1 and caveolin-2 in regulation of Ca2+ responses to bronchoconstrictors such as acetylcholine and histamine, and in Ca2+ influx via store-operated calcium entry (SOCE) channels (STIM1, Orai1, TRPC isoforms). Using siRNA, overexpression vector, knockout mouse and fluorescence confocal imaging technologies, we are determining whether airway inflammation (e.g., with TNFα or IL-13) influences caveolin expression/localization and integration of Ca2+ and force responses.
2. Mitochondria in Ca2+ Regulation. Mitochondria can buffer elevated cytosolic Ca2+, especially under pathological conditions of Ca2+ overload. In ongoing studies, we are investigating the contribution of specific mitochondrial Ca2+ regulatory mechanisms (Ca2+ uniporter, Na+/Ca2+ exchanger, Ca2+/H+ exchanger) in regulation of cytosolic Ca2+ in human ASM cells. Using 2-color fluorescence Ca2+ imaging as well as markers for mitochondrial energetics, we are examining the interactions between mitochondria and mechanisms such as SOCE, IP3, and ryanodine receptor channels.
3. Developmental Changes in Airway. The mechanisms underlying pediatric asthma may be different from those causing asthma in adults. Using human and animal tissues, we are currently exploring developmental differences in mechanisms that regulate airway tone. For example, changes in caveolin protein expression and caveolar regulation of intracellular Ca2+ responses to agonist stimulation are being studied using multiple, convergent techniques. The effects of airway inflammation on mechanisms that regulate smooth muscle cell proliferation and cell death are being explored.