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. The laboratory is currently focused on the following aspects of Ca2+ regulation (and dysregulation) in ASM:
- Neurotrophins in the Airway. Neurotrophins are growth factors known to influence the structure and function of neurons. We have recently discovered that neurotrophins are expressed in airway smooth muscle, and that some neurotrophins (BDNF and NT4 acting via TrkB) enhance bronchoconstrictor responses while others (NT3, acting via TrkC) inhibit responses. Based on these exciting data, we are using biochemistry, molecular biology, and Ca2+ imaging to investigate the ASM signaling mechanisms activated by TrkB and TrkC, especially those dealing with Ca2+ regulation (SOCE, sarcoplasmic reticulum, mitochondria), force regulation (rho-kinase), and cell proliferation and survival (PI3/Akt, Erk1/2). These studies are being extended to interactions between neurotrophins and inflammatory cytokines such as TNFα and IL-13, and with smoking and secondhand smoke exposure.
- Cigarette Smoke Exposure and the Airway. Both smoking itself and secondhand smoke exposure are known risk factors for airway diseases including lung cancer. We are currently examining changes in airway smooth muscle structure and function induced by cigarette smoke exposure using both human tissues and, in collaboration with the Department of Pulmonary Medicine, mouse models of smoke exposure. Signaling mechanisms such as neurotrophins, cytokines, and gasotransmitters such as carbon monoxide and hydrogen sulfide are being examined.
- Sex Steroids and Airway Tone. The incidence and severity of asthma and reactive airway disease differs between men and women. Menarche, pregnancy, and menopause as well as use of estrogen replacement therapy can influence the incidence and severity of symptoms. We are currently exploring how estrogens can influence the tone of airway smooth muscle by characterizing the intracellular signaling pathways modulated by estrogen receptor stimulation at the plasma membrane as well as in the nucleus. The focus is on regulation of intracellular Ca2+ as well as proliferation of airway smooth muscle cells with inflammation.