Project 461830

If healthy people are prohibited from taking deep breaths or deep inspirations (DI) for ~30 min, they will develop asthma-like symptoms. Fortunately, these symptoms will disappear once they are allowed to take in deep breaths again. One consistent feature of asthma is that the airways do not relax in response to DI, as in healthy people. It is not clear why DI is so effective in relaxing the airways of non-asthmatics but so ineffective in asthmatics. Unraveling the mechanisms that cause these differences in how healthy and asthmatic lungs respond to lung inflation will lead to a better understanding of how to treat asthma. We believe that restoring the DI-induced airway relaxing response is a viable treatment strategy to alleviating asthma symptoms. There are several candidate mechanisms that could explain the beneficial effects of DI. We will first focus on how airways respond to lung inflation in non-asthmatics: how much are the airways stretched during DI and to what degree is the contractility compromised by the DI-associated stretch. We will then focus on asthmatic airways to determine whether the airways are stretched to the same extent as they are in non-asthmatics during a DI and whether this stretch leads to a decrease in contractility of the muscle cells. We know an enzyme called Rho kinase (which enhances airway muscle contraction) whose activity is increased in asthmatics. We will test whether inhibiting Rho kinase can restore the DI-induced airway relaxing response in asthmatics. An important strength of this proposal is the use of asthmatic and non-asthmatic human donor lungs that allows the results to be incorporated directly into any translational strategies aimed at improving treatment of the disease.