Recent studies have suggested that respiratory muscle dysfunction due to excessive respiratory muscle loading and/or shock (septic, cardiogenic) may contribute to the development of respiratory failure in patients with cardiopulmonary diseases. The mechanisms by which these various stresses produce alterations in muscle function are, however, poorly understood. While studies of other vital organs have suggested that many forms of stress act to induce free radical mediated tissue damage, the role of free radicals in mediating diaphragmatic dysfunction has not been examined. The purpose of the present proposal is to examine the role of free radicals in producing diaphragmatic dysfunction in response to three clinically important stresses; fatiguing levels of rhythmic contraction, protracted ischemia, and sepsis. All experiments will be performed in animal models employing cats and dogs. In Objective I we will examine the role played by free radicals in modulating the development of diaphragmatic fatigue. We will examine the effect of several free radical scavengers (SOD, catalase, DMSO) on measures of diaphragm contractile performance (twitch kinetics, force frequency relationship, action potential transmission) and oxygen utilization (blood flow, oxygen extraction, oxygen consumption) over time during fatiguing contractions. Two indices of free radical generation (tissue conjugated diene and MDA levels) will also be examined in these studies. We will study this issue both in the electrically stimulated diaphragm (this permits precise control of diaphragmatic activation) and in the spontaneously driven diaphragm during inspiratory loading. Objective II studies will examine the effect of several free radical scavengers on the diaphragmatic response to endotoxin. These studies will assess changes in contractile function, vascular reactivity, oxygen extraction, and tissue MDA and conjugated diene levels over time in endotoxin treated animals with and without free radical scavenger pretreatment. In Objective III we will examine the role of free radicals in inducing ischemia/reperfusion injury in the diaphragm. These studies will characterize the injury induced by ischemia/reperfusion (i.e. effects on strength, fatiguability, vascular reactivity, oxygen extraction, alterations in tissue MDA and conjugated diene levels) and the effect of free radical scavengers on this form of injury. The stresses to be examined in these experiments represent important clinical causes of diaphragmatic dysfunction and respiratory failure. The studies outlined in this grant may provide important information regarding the pathogenesis of these forms of diaphragmatic dysfunction and may lead to new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL038926-06
Application #
2219115
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1987-07-01
Project End
1996-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Nethery, D; Callahan, L A; Stofan, D et al. (2000) PLA(2) dependence of diaphragm mitochondrial formation of reactive oxygen species. J Appl Physiol 89:72-80
Supinski, G; Nethery, D; Stofan, D et al. (1999) Oxypurinol administration fails to prevent free radical-mediated lipid peroxidation during loaded breathing. J Appl Physiol 87:1123-31
Supinski, G; Nethery, D; Stofan, D et al. (1999) Extracellular calcium modulates generation of reactive oxygen species by the contracting diaphragm. J Appl Physiol 87:2177-85
Supinski, G; Nethery, D; Stofan, D et al. (1997) Effect of free radical scavengers on diaphragmatic fatigue. Am J Respir Crit Care Med 155:622-9
Supinski, G; DiMarco, A; Dibner-Dunlap, M (1994) Alterations in diaphragm strength and fatiguability in congestive heart failure. J Appl Physiol 76:2707-13
Supinski, G S; Stofan, D; Nashawati, E et al. (1993) Failure of vasodilator administration to increase blood flow to the fatiguing diaphragm. J Appl Physiol 74:1178-85
Supinski, G; Nethery, D; DiMarco, A (1993) Effect of free radical scavengers on endotoxin-induced respiratory muscle dysfunction. Am Rev Respir Dis 148:1318-24
Supinski, G S; Dick, T; Stofan, D et al. (1993) Effects of intraphrenic injection of potassium on diaphragm activation. J Appl Physiol 74:1186-94
Supinski, G; Stofan, D; DiMarco, A (1993) Effect of ischemia-reperfusion on diaphragm strength and fatigability. J Appl Physiol 75:2180-7
Shindoh, C; Dimarco, A; Nethery, D et al. (1992) Effect of PEG-superoxide dismutase on the diaphragmatic response to endotoxin. Am Rev Respir Dis 145:1350-4

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