Description

The purpose of this project is to investigate the consequences of smoke exposure on the diaphragm weakness that is developed during prolonged mechanical ventilation (MV) in mice. While MV can be a lifesaving clinical practice, extended periods of time on MV can lead to atrophy and contractile dysfunction of the diaphragm, known as ventilator-induced diaphragm dysfunction (VIDD). The hypothesis is that smoking will lead to an acceleration in myofiber oxidative stress, as well as increased protein breakdown in the diaphragm, which speeds up the rate at which mice develop VIDD. Wild-type, adult (12 weeks old) mice (n=8 per group) will be either exposed to cigarette smoke (CS) daily for 2 months or non-exposed. After the 2-month CS exposure, MV will be performed in mice for either 2 hours, 6 hours, or not ventilated as the control, using a small animal ventilator. After doing so, angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AT1R) activity in diaphragm myofibers will be measured. These will be tested because plasma Angiotensin II (Ang II) is expected to increase, enhancing AT1R activity in the diaphragm, accelerating VIDD during MV. Following the in vivo MV, ex-vivo diaphragm force contractility, muscle histology changes, cytokine levels, and Ang II signaling will be measured. While there has been research to suggest that CS exposure leads to muscle contractile dysfunction before developing lung disease, there isn’t any research that investigates diaphragm weakness that is developed from CS exposure during MV. The end goal of this research is to clarify the mechanism of diaphragm weakness that comes from MV in smokers. This information can be used to better understand and possibly minimize the effects of VIDD. At the moment of submission, the MV system has been tested, and the first group of mice are soon subject to MV.