Treatments sought to counter inflammation in many diseases
This article first appeared in the St. Louis Beacon: Inflammation is a major aspect of many chronic diseases, ranging from some heart conditions to epilepsy, scientists and researchers are discovering. And as they have learned more, they have realized that inflammation causes much more damage than formerly thought.
What is inflammation? It is the body’s response to a noxious stimulus; picture that painful red swelling around a bacteria-laden splinter.
More broadly, inflammation is the body’s response to injury or destruction of tissue. The inflammatory response follows a predictable pattern. First, specific cells in the tissues recognize foreign invaders like microorganisms. These cells also recognize byproducts coming from the body’s own injured cells.
The resident cells then send out chemical signals to attract white cells — the fighting cells of the blood — while other chemical signals direct the white cells to the site of injury.
These chemical signals are small molecules called pro-inflammatory cytokines. Cytokines can initiate many processes, including producing molecules that cause pain.
Greatly simplified, the first wave of white cells begins to attack and ingest invading organisms. They also secrete more pro-inflammatory cytokines, including some that finish the cleanup.
In the well-oiled inflammatory machine, soon after reaching the injury the first wave of white cells sets the healing process in motion. They secrete anti-inflammatory cytokines — a different set of small molecules that promote death and cleanup of the warrior white cells and stop collateral damage tissue destruction.
The process is very old. As Dr. Douglas Mann, chief of cardiology at Washington University Medical School, points out, it began to evolve in organisms as primitive as protozoans, with short life spans. For them a short emergency response was sufficient.
Human beings, on the other hand, live for a long time. The complex inflammatory program tends to develop weaknesses with time. It may not get completely turned off. And so a process that was supposed to be an emergency repair becomes a chronic condition.
Medicine today is beginning to take inflammation into account in devising treatments. Even when it does not cause the disease, in some cases like epilepsy, inflammation may worsen the disease, and treatment with anti-inflammatory drugs may be useful.
In other cases, as with lupus, inflammation is responsible for disease symptoms, but they must be treated with immune suppressors and steroids. With some cancers, inflammation can be a cause or a co-factor. But, in other cases, as with type II diabetes or Alzheimer’s, the role of inflammation is still under investigation.
The role of inflammation in Alzheimer’s disease is quite complicated, says Dr. John C. Morris, professor of neurology at Washington University School of Medicine. The pathological marker of Alzheimer’s is the "senile plaque," or tangles of a protein called b-amyloid. Brains with an abundance of these plaques show inflammatory activation of cells called microglia.
These microglia are analogous to the scavenging white cells of the blood. When activated they try to attack and remove the lesions and lesion-containing cells. In the process they secrete reactive oxygen, protein-destroying enzymes, and pro-inflammatory cytokines.
As in other inflammatory situations, the destruction caused by the cytotoxic substances does not discriminate between diseased and normal cells.
Past epidemiological studies showed that people with rheumatoid arthritis — and who therefore routinely use anti-inflammatory drugs — may have a lower risk of developing Alzheimer dementia. However, use of anti-inflammatory medicines has not been successful in patients with Alzheimer dementia.
“There is no current evidence to support taking anti-inflammatories to either prevent or treat Alzheimer dementia,” says Morris.
He suggests that in light of the repeated failures of single drugs against amyloid plaques to benefit people with Alzheimer dementia, future treatments should combine drugs, one of which may well be an anti-inflammatory agent.
About one in every 200 people has epilepsy, reports Dr. Jacqueline French of New York University. It is more common than Parkinson’s, multiple sclerosis and ALS combined. In fact, according to an Institute of Medicine report, one in 23 people will have active epilepsy at some point in their lives. Yet because of a stigma attached to seizures, this condition is often thought to be rare.
Epileptic seizures can have many causes, but inflammation in the brain after seizure seems to be nearly universal.
Patients with severe epilepsy originating in a focal area of the brain may have that area surgically removed. Pathology of these lesions shows inflammatory cells and pro-inflammatory cytokines not present in normal brains. One investigator has shown that the number of inflammatory cells is higher if the last seizure came shortly before surgery. Animal models are consistent with human pathology, and anti-inflammatory drugs will quiet down the seizures.
In epilepsy, then, inflammation is a result of seizure. The inflammatory process apparently sensitizes the neurons so that they are more excitable. Says French, “We believe this is a vicious cycle. Inflammation from the first seizure contributes to the next seizure.”
She is currently studying the effects of an experimental drug that inhibits the production of a particular pro-inflammatory cytokine. The drug gave promising anti-seizure results in animal models. Testing in humans has now progressed to stage 2b, meaning that the drug seems to be safe.
Since post-seizure inflammation appears common to all forms of epilepsy, success with the experimental drug would be very exciting to French because they might be able to help a great variety of patients.
Cancer is a term used to classify a huge spectrum of diseases. It makes sense that inflammation plays different roles depending upon the type of cancer.
Physicians have long been aware that the risk of colon cancer is significantly reduced in people who regularly take non-steroidal anti-inflammatory drugs like aspirin or ibuprofen.
As Dr. Siobhan Sutcliffe, assistant professor of surgery at Washington University Medical School, explains, inflammation is a primary cause of some cancers while in others it is a co-factor.
Some infections set up persistent inflammation that leads to cancer. Helicobacter infections in the stomach and hepatitis B and C in the liver are both risk factors for developing cancer. (Helicobacter is the bacterium that causes stomach ulcers.) If the inflammation persists, then some by-products such as oxygen radicals will with time damage the DNA. Some changes in a cell’s DNA can lead to cancer.
Inflammation can also be a co-factor. Infection with human papillomavirus (HPV) is a risk factor for cervical cancer. But not everyone infected with HPV develops cancer. HPV infection itself is not inflammatory, but HPV-infected patients who have also contracted chlamydia are at significantly higher risk for cervical cancer. Chlamydia causes inflammation, thought to be a co-factor in the development of this cancer.
Heart attacks are most often the end result of an inflammatory process.
Inflammation causes the plaques that characterize atherosclerosis (narrowing of the arteries caused by fatty deposits). The original insult is excess low density lipoprotein (LDL) cholesterol in the blood. Resident blood vessel scavengers called macrophages take up LDL and become "foam cells."
These activated foam cells accumulate in the vessel walls, forming the "fatty streaks" of atherosclerotic plaques. They also send out pro-inflammatory cytokines that recruit more activated white cells whose secretions may cause the plaque to rupture. Rupture can lead to a blood clot.
If a blood clot blocks circulation to a tissue, the tissue will begin to die.
A blood clot in a coronary artery causes a heart attack, during which cardiac tissue dies. The dead cells release their contents, many of which bind to specific receptors that initiate inflammation.
Ideally, the inflammatory progression will get rid of the dead and dying tissue with a minimum of damage to healthy tissue and healing will begin. Unfortunately, Mann points out, most heart attacks occur in older people who may have problems in turning off inflammation.
The low-dose baby aspirin that many older adults take routinely inhibits clotting, but is not large enough to be anti-inflammatory. The usual non-steroidal anti-inflammatory drugs such as naproxin and ibuprofen are not used either to prevent or to treat heart attacks. Statin drugs may have some anti-inflammatory properties in addition to lowering LDL cholesterol.
Systemic Lupus Erythematosis
Lupus, the most common disease of young women in the United States, is an autoimmune disease. For reasons unknown, the body makes antibodies to itself rather than invaders.
Once antibody complexes settle in a tissue, they set up an inflammatory process that attacks the tissue. White cells are recruited, and they release destructive enzymes. The destructive enzymes create more products that promote even more inflammation with its attendant tissue destruction.
Treatment with anti-inflammatory drugs does not help lupus patients. As Dr. Terry Moore, director of rheumatology at Saint Louis University School of Medicine, puts it, “The immune system is too revved up.” These patients must be treated with the same type of immune-suppressing agents used for transplant patients.
Interestingly, an anti-malarial drug called hydroxychloroquine helps most lupus patients. This drug stabilizes the membranes that surround many of the protein-destroying enzymes. When the destructive enzymes are sequestered, less tissue is destroyed, and fewer pro-inflammatory molecules are released.
Type 2 diabetes
The role of inflammation in type 2 diabetes is still controversial, explains Dr. Fumihiko Urano, Schecter professor of medicine at Washington University School of Medicine. He believes that low-grade chronic inflammation plays a role in the progression of the disease, but much of the evidence is indirect.
Most of the evidence comes from studies involving a pro-inflammatory cytokine called IL-1 in the pancreas. In experiments, this molecule has been shown to harm the pancreatic b-cells that produce insulin.
A double-blind study in which patients were treated with an antagonist to the IL-1 receptor showed better b-cell function.
Physicians disagree on whether type 2 diabetic patients should be treated with aspirin. Although some trials did show improvement of blood glucose levels when patients were given high doses of aspirin, those same doses can cause stomach bleeding. Salsalate, a precursor molecule in aspirin synthesis is anti-inflammatory, but does not cause bleeding. A recent clinical trial show this drug worked well in treating type 2 diabetes.