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Depression and Inflammation may go Hand-in-Hand

By HBC Protocols August 31, 2006 0 comments

People who are depressed are more likely to have exaggerated inflammatory responses to stressful situations, according to the results of a study released this week. Now, researchers want to know if that inflammation is behind the link between depression and heart disease … or if it’s the actual cause of depression.

Investigators from Emory University in Atlanta studied 28 otherwise healthy men. Half of the participants were diagnosed with major depression while the other half was depression-free. When faced with stressful situations, inflammatory markers in the blood rose in both the depressed men and the healthy controls, but levels were much higher in the men with major depression.

The depressed men in the study were more likely to have a history of early life stress as well, which could have contributed to the depression-inflammation link.”While inflammation is essential for us to fight bacterial and viral infections, too much inflammation can cause harm,” reports study author Andrew Miller, M.D. “There’s always some collateral damage when the immune system gets fired up, and we now believe that too much inflammation, either at rest or during stress, may predispose people to become depressed or stay depressed.”

The link between inflammation and depression could also help explain why people with depression are more likely to suffer from heart disease, diabetes, and other conditions that have been linked to an increased inflammatory response. Major depression is considered the leading cause of disability in countries all over the world. Costs associated with the condition in the United States come in at around $70 billion a year.

SOURCE: American Journal of Psychiatry, published online Sept. 1, 2006

Inflammation

Inflammatory diseases afflict millions of people across the world leading to suffering, economic loss and premature death. As well as inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), other diseases include allergic rhinitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and psoriasis.

Billions of dollars are being spent by pharmaceutical and biotechnology companies to identify and develop innovative therapeutics to treat such diseases. Over the last few years, despite intensive global research cures have still not been found.

Inflazyme has unique technology and products that we believe could be developed as novel therapies to treat a range of inflammatory diseases in particular those affecting the lungs such as asthma, COPD, allergic rhinitis and possibly cystic fibrosis. Clinical studies have shown that our drugs, called LSAIDs™ (leukocyte selective anti-inflammatory drugs), affect certain components of the inflammatory process leading to a reduction in the symptoms of inflammation and improvement in the patient’s quality of life.

What is inflammation?

Inflammation is part of the healthy body’s natural defense system. It is a process whereby the body’s cells and natural chemicals protect us from physical damage and infection from foreign substances such as bacteria and viruses.  White blood cells, or leukocytes, are the body’s major infection-fighting cells. The primary objective of inflammation is to isolate, localize and eradicate foreign substances and repair damaged tissues.

Types of Inflammation – Acute and Chronic

Acute inflammation is short-lasting, from a few minutes to a few days, and it may be caused by physical damage, foreign substances, micro-organisms or other agents. Common examples of inflammation include sore throat or skin reactions such as a scratch, a burn, an insect bite. Viral infections can also give rise to acute inflammation.

Chronic inflammation is an inflammatory response lasting for several weeks, months or even years. It may arise as a result of acute inflammation and often the two co-exist.  The exact nature, extent and duration of chronic inflammation is highly variable, and it frequently depends on a balance between the agent causing the inflammation and the attempts of the body to remove it. Examples of chronic inflammation include COPD, tuberculosis, arthritis, inflammatory bowel disease and Chrohn’s disease.

What are some of the symptoms of inflammation?

Irrespective of whether the inflammation is acute or chronic, the range of symptoms is usually the same:

  • Redness
  • Warming and swelling of affected tissues
  • Fever
  • Pain

Other symptoms may include the following, but only one or two are experienced at the same time:

  • Fever
  • Chills
  • Fatigue/loss of energy
  • Headaches
  • Loss of appetite
  • Muscle stiffness
  • Joint pain, stiffness or loss of function

The inflammatory response consists of changes in blood flow, increased permeability of blood vessels and escape of cells from the blood into the tissues. The changes are essentially the same whatever the cause and wherever the site.

What causes the symptoms of inflammation?

Tissue damage or detection of a foreign substance triggers white blood cells to release chemicals into the blood or affected tissues thus initiating the inflammatory process.  The release of these chemicals increases the blood flow to the area of injury or infection and may result in redness and warmth.  This increased blood flow allows for additional white blood cells to be recruited to the area of inflammation, which in turn release more chemicals, recruiting more white blood cells, and so on, and so on.

Some of these chemicals also initiate a process in which the white blood cells and fluid are transported out of the blood stream to the site of inflammation. This movement of cells and fluid from the bloodstream into the surrounding tissues usually results in swelling and this protective process may also stimulate the nerves causing pain.

In a healthy individual, when the infection has been cleared or the tissue damage has been healed, the inflammation process stops, and the body returns to its normal state. 

In some people, however, the body’s immune system attacks itself by mistake. These conditions, called autoimmune disorders, lead to a state where the inflammatory response remains “turned on” resulting in potentially significant damage to the body’s tissues.

Asthma

In the case of asthma, persistent inflammation exists in a sufferer’s lungs. The ongoing inflammation leads to increased sensitivity of the lung tissue. The airways become unusually sensitive to external stimuli, such as changes in temperature and environmental factors (animal dander, pollen, etc.). This increased sensitivity may lead to an asthma attack where the tightening of the airways in the lungs makes something as simple as breathing difficult. In very severe cases, breathing is impossible without immediate medical intervention.

Our LSAIDs™ therapeutics have shown anti-inflammatory effects in clinical studies in people suffering from asthma. We believe their mode of action is related to blocking key aspects of the inflammation cascade, specifically blocking a component of the leukocyte adhesion cascade shown in Figure 1. Moreover, we have observed that the LSAIDs™ appear to preferentially accumulate in lung tissues. Hence, our research and development efforts are directed towards inflammatory diseases of the lung such as asthma, COPD and allergic rhinitis.

A Molecular Glance at Inflammation – the Leukocyte Adhesion Cascade

This cascade involves a very specific sequence of events that takes place at the molecular level of the inflammatory response irrespective of whether a person is suffering from acute or chronic inflammation. The process involves the recruitment of leukocytes to the sites of inflammation. The diagram below shows the steps involved.  We believe the LSAIDs™ have their effect within this cascade by inhibiting part of this process, resulting in a reduction in the number of leukocytes migrating into the surrounding tissues, and thus reducing the unwanted inflammation.

The Leukocyte Adhesion Cascade

Endothelium: The endothelium is a thin layer of flat cells located at the interface between the blood and the vessel wall. These cells are in close contact and form a slick layer preventing the interaction of blood cells with the vessel wall.

Activation: An infection, or some sort of tissue damage, triggers the release of compounds leukocytes to move into tissue towards the foreign invader.

Margination: The process in which free-flowing leukocytes exit the central blood stream, and initiate leukocyte and endothelial cell interactions by close mechanical contact.

Rolling: Once leukocytes are in contact with the endothelium, they may transiently adhere to cellular components on the endothelium and begin to roll.

Adhesion: As the rolling rate slows, the components on the outside of the leukocyte may bind to adhesion molecules on the endothelium, causing the leukocyte to adhere tightly to the endothelium.

Transmigration: This is the migration of the adhered leukocyte between adjacent endothelial cells to the underlying tissue.


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