Team:UCL/Lungs
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Lungs: Superoxide Dismutase Gene therapy
Over expression of antioxidants that break down toxic reactive oxidative species into less harmful hydrogen peroxide. Read more about our novel synthetic biology approach to the prevention of age-related diseases to the lungs.
Ageing of lungs: the problem
As you get older, you lose the ability of your major organs working at their maximum function. One of these important organs being the lungs. The effects of aging on the respiratory system are similar to those that occur in other systems: there is a decrease in peak airflow and gas exchange and a decline in the effectiveness of lung defence mechanisms. These changes contribute somewhat to an older person's reduced ability to do vigorous exercise, especially intense aerobic exercise. More importantly, these age-related changes in the lungs lead to the development of age related diseases and eventually death.
One of these age related diseases being chronic obstructive pulmonary disease (COPD) that and leads to chronic inflammation and progressive destruction of lung tissues. Its currently a major public health problem worldwide and is the 4th leading cause of death in the world.
What actually causes your lung cells to age?
Increasing evidence is showing that we accumulate toxins as we age and this is one of the contributing factors that lead to the ageing of our cells. One toxin being free radicals. As our cells burn food, they also generate toxins known as free radicals, that damage every part of our cells, literally bombarding them millions of times per second, damaging all cells. The result: oxidative stress. Because of their anatomy, location and function, the lungs are highly susceptible to oxidative damage. Increasing evidence suggests that oxidative damage of lung cells due to ageing leads to the onset of these age related disease like COPD.
Reactive oxygen species (ROS) are free radicals that are generated during oxidative phosphorylation. They have various physiological roles and are removed rapidly from the body [1]. Many papers have suggested that the overproduction of ROS causes DNA damage, cell dysfunction, cell death which lead to the ageing of a cell. Overproduction of ROS is also associated with pathogenesis of some age related diseases including cardiovascular diseases, neurological disorders, and pulmonary diseases [2] . An imbalance between generation of ROS and antioxidant defences leads to oxidative stress in which cell antioxidants are at an insufficient level to keep ROS below a toxic threshold [1].
Natural defences in the body
Naturally your body produces antioxidants that break down harmful toxin free radicals into less harmful substances like h202. It’s been found that in imbalance in the amount of ROS and antioxidants leads to the damage of a cell therefore leading it to age. Superoxidise dismutase (SOD) is an important antioxidant enzyme in nearly all living cells exposed to oxygen and is present inside and outside the cell membrane.
Figure 3: Image showing that there needs to be a balance in the amount of antioxidants and oxidative stress to not cause ageing of cells.
SOD enzyme’s catalyses the reaction O-2 + O-2 + 2H+ → H2O2 + O2.
There are three types of SOD enzymes:
- SOD1 (Soluble - CuZnSOD) – Involved in removing oxidative stress causing ischemia-reperfusion injury and ischemic heart disease.
- SOD2 (Mitochondrial - MnSOD) - SOD2 clears mitochondrial reactive oxygen species (ROS).
- SOD3 (Extracellular - ECSOD) - protect the brain, lungs, and other tissues from oxidative stress.
Some examples of antioxidant enzymes naturally found in cells are: SO1, SOD2 and SOD3 (Extracellular - ECSOD) - protect the brain, lungs, and other tissues from oxidative stress. SOD3 is an antioxidant and anti-inflammatory protein found in both lung tissue and in the lung lining fluids.
SOD3 is found in the extracellular matrix of tissues and is ideally situated to prevent cell and tissue damage initiated by extracellularly produced ROS. It is also the primary extracellular antioxidant enzyme found in the lungs and protects the extracellular matrix during lung injury.
SOD3 is found in the extracellular matrix of tissues and is ideally situated to prevent cell and tissue damage initiated by extracellularly produced ROS. It is also the primary extracellular antioxidant enzyme found in the lungs [2] and protects the extracellular matrix during lung injury [4] [5] [6]. It’s been found that mutations in the SOD3 protein is associated with reduced lung function in adults [7] and lung function decline in chronic obstructive pulmonary disease (COPD) [8] [9]. Because of their anatomy, location and function, the lungs are highly susceptible to oxidative damage. [1] One study also showed that SOD3 levels decreased as the mice aged in the lungs [10] . ROS are mainly produced by phagocytes as well as by the alveolar, bronchial and endothelial cells. Increased oxidant levels and decreased antioxidant defences can contribute to the progression of idiopathic pulmonary fibrosis and other lung diseases. Chronic obstructive pulmonary disease (COPD) is an age related diseases that is also a major public health problem worldwide (fourth leading cause of death in the world) and leads to small airway inflammation, fibrosis and alveolar wall destruction [11] . It is thought that COPD is stimulated by free radicals from cigarette smoke, which lead to chronic inflammation and progressive destruction of lung tissues. COPD prevalence rises with increasing age and SOD3 is an antioxidant and anti-inflammatory protein found in both lung tissue and in the lung lining fluids.
ROS accumulate as we age [3], therefore the overexpression of SOD is one potential way to decrease the levels free radicals that accumulate.
