Diaphragm Fatigue Prevention in Emphysema

University Of Arkansas At Fayetteville, Fayetteville AR

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): Emphysema (EMP) is characterized by permanent destruction of alveolar walls leading to static hyperinflation due to loss of lung elastic recoil and dynamic hyperinflation due to incomplete lung emptying that imposes a persistent load on the diaphragm and impairs its mechanical efficiency. With acute exacerbations, a complex interplay of biophysiologic processes including oxidative stress and dysruption in mitochondrial function can lead to diaphragm fatigue (DF) and respiratory failure. The objective of this study is to determine if exercise conditioning and pharmacological improvement of diaphragm muscle function with intravenous infusions of dobutamine (DOB) are effective in abating the development of DF in EMP. This study may offer valuable information concerning complex dynamics of DF that could have important implications for application of strategies including exercise training and pharmacologic therapies to prevent development of respiratory failure. The aims of this study are to investigate the 1) effect of exercise conditioning in abating DF, 2) impact of exercise conditioning on oxidative stress and mitochondrial function during DF, 3) use of DOB in preventing DF and, 4) effect of DOB administration on oxidative stress and mitochondria! function during DF. Four groups of Golden Syrian hamsters will be randomly assigned to: Group 1-saline/sedentary (SS); Group 2- saline/exercise (SE); Group 3-emphysema sedentary (ES); and Group-4 emphysema exercise (EE). EMP will be induced by intratracheal instillation of crystalline porcine pancreatic elastase. Following a 3 month post-operative period, Groups 2 and 4 will enter a 12 week exercise conditioning program consisting of progressive treadmill training with incremental increases in speed and inclination until 18 m/min for 1 hour/day, 5 days per week at a 5% incline has been reached. Within 48 hours following the last training session, DF will be produced through respiratory resistance loading (IRL). Three experimental periods will be used: period 1- baseline; period 2- application of IRL and administration of DOB or physiologic saline; and period 3-30 minutes of DF. Diaphragm shortening, cardiac output, diaphragm blood flow, heart rate, respiratory rate and arterial blood gas values will be monitored following each period. Following the experiment, the diaphragm will be quickly harvested and GSH/GSSG and mitochondrial isolation and assay performed. [unreadable] [unreadable] [unreadable]