Role of oxidative stress and mitochondria in COPD
Initial Award Abstract
Long term cigarette smoking is known to cause lung damage, destruction, and disease. A majority of chronic smokers will eventually develop Chronic Obstructive Pulmonary Disease (COPD). Emphysema and bronchitis are examples of COPD. This disease is associated with loss of lung tissue and breathing difficulties. COPD is one of the leading causes of death and disease worldwide. The 2006 report released by the Global Initiative for COPD states that the worldwide death rates from COPD are expected to rise from the sixth leading cause of death from 1990 to the third leading cause by 2010. While COPD remains a major health problem worldwide, how cigarette smoke causes lung damage and CODP remains unknown.
It is well established that cigarette smoke contains many toxic and reactive chemicals (tar, oxidants, nitric gases, etc) that can harm the lungs. We propose that oxidants and other toxic chemicals in cigarette smoke damage important proteins in the lung, as part of the progression of disease. In particular, we suggest that cigarette smoke damages proteins in mitochondria. This may be a key event in emphysema. Mitochondria are small organelles in cells that are responsible for most of the energy production in our body that is essential for life. This damage of proteins in mitochondria –caused by cigarette smoke– leads to severe dysfunction of these organelles, thus compromising energy levels. First, because mitochondria are the powerhouses of the cell, damage to mitochondrial proteins by cigarette smoke would cause energy production in lungs to drop. This could inhibit normal lung function, as well as essential repair processes. Because the toxins in cigarette smoke are constantly causing lung damage, any decrease in cell repair could accentuate lung injury. Second, mitochondria also control a process called “apoptosis” or programmed cell death. If mitochondria are damaged, cell death pathways will become activated and lung cells will begin to die. Lung cell death is an important component of emphysema and other COPD. Finally, mitochondrial damage can enhance free radical production. Free radicals are toxic molecules that are formed during metabolism. Our body has numerous antioxidants like vitamin E that combat free radicals generated by mitochondria during normal metabolism. However, if mitochondria are damaged, they often generate large quantities of free radicals that can overwhelm our antioxidant defense system and cause damage to protein and other important macromolecules in cells. Our proposal thus focuses on the idea that cigarette smoking leads to damaged proteins in mitochondria and hence triggers (a) a loss in energy production in the lung, (b) activation of cell death pathways that kill off lung cells, and (c) increase generation of free radicals that further damages the lungs. We believe all these factors together trigger lung damage and ultimately cause emphysema. Using novel techniques to analyze protein damage, we hope to identify the key proteins in mitochondria that damaged by cigarette smoke.
Functional mitochondria are essential for good health. An important antioxidant that keeps mitochondria healthy and protects it from damage is glutathione (GSH). Some studies have shown that cigarette smoke can deplete GSH in cells, and leave mitochondria vulnerable to free radical attack. Part of our proposal is aimed at finding therapeutics strategies to increase GSH levels and keep mitochondria healthy. We will test whether nutritional supplements like lipoic acid and N-acetyl cysteine (NAC), which increase GSH levels in lungs, can prevent mitochondria damage and protect lungs from cigarette smoke. If our hypothesis is correct, lipoic acid and NAC by increasing GSH in the lungs will protect mitochondria from cigarette smoke and ultimately decrease lung damage and disease. We hope the findings from our study will lead to new therapies that prevent or treat emphysema and other cigarette smoke related diseases. |
|Short-term cigarette smoke exposure induces reversible changes in energy metabolism and cellular redox status independent of inflammatory responses in mouse lungs
|Periodical: American Journal of Physiology. Lung Cell Molecular Physiology.
|Authors: Agarwal, A.R., Zhao, L., Sancheti, H., Sundar, I., Rahman, I., and Cadenas, E.