Inflammation is a response of a tissue to injury, often injury caused by invading parasites. It is characterized by:
1. increased blood flow to the tissue causingA bacterial infection initiates inflammation through several interconnecting mechanisms:
2. increased temperature,
3. redness,
4. swelling, and
5. pain.
- The "nonself" surface of bacteria allows the complement system to be
activated through the "alternative pathway". - Specific surface molecules of the bacteria, called Pathogen-Associated Molecular Patterns (PAMPs) bind to Toll-like receptors (TLRs) on or in a variety of leukocytes.
Mast Cell
- Their cytoplasm is loaded with granules containing mediators of inflammation.
- Their surface is coated with a variety of receptors which, when engaged by
the appropriate ligand, trigger exocytosis of the granules.
- Their Toll-like receptors trigger exocytosis when they interact with PAMPs like the lipopolysaccharide (LPS or "endotoxin") of Gram-negative bacteria (TLR-4) the peptidoglycan of Gram-positive bacteria (bind TLR-2)
- Their receptors for complement fragments trigger exocytosis when they bind C3a and C5a bacteria coated with C3b
- some immediately as they discharge their granules
- some later as they synthesize them by new gene transcription
- recruiting all the types of white blood cell to the site monocytes that become macrophages when they leave the blood and enter the tissue
- neutrophils
- antigen-presenting dendritic cells
- all kinds of lymphocytes:
*B cells and T cells, leading to an adaptive immune response;
*NK cells (an effector cell in innate immunity). - eosinophil
- activating many of these recruited cells to produce their own mediators of inflammation.
I shall not attempt to catalog all the players, but here are some of the major (and best understood) ones.
Neutrophils
Eosinophils
Tumor Necrosis Factor-alpha (TNF-α)
Large amounts of TNF-α are quickly released by stimulated mast cells. All the cells involved in inflammation have receptors for TNF-α, and are activated by it to synthesize more on their own. This positive feedback quickly amplifies the response.
Link to a description of how the binding of TNF-α to its receptors on a responding cell initiates new gene transcription by the cell.
Chemokines
These are chemotactic cytokines; that is, secreted proteins that attract other leukocytes into the area. Several have been identified.
Reactive Oxygen Species (ROS).
These are produced by activated phagocytes: macrophages and neutrophils. They are toxic for microorganisms but can also lead to tissue injury. ROS are described in detail on another page. Link to it.
Histamine.
The granules of mast cells are loaded with histamine and their exocytosis releases this potent mediator. Histamine increases the blood flow to the area and the leakage of fluid and proteins from the blood into the tissue space. Thus the quick release of histamine is largely responsible for the redness and swelling associated with inflammation.
Interleukin-1 (IL-1).
Macrophageand
Monocytes
Macrophages and monocytes are the main source of this cytokine. IL-1 has both:
- paracrine effects on cells in the vicinity, e.g., causing them to produce
tissue factor and thus triggering the blood clotting cascade. [Link} stimulating
the synthesis and secretion of a variety of other interleukins helping to
activate T cells and thus initiate an adaptive immune response
endocrine (hormonal) effects as it is carried in the blood throughout the body. - decreasing blood pressure inducing fever. IL-1 causes fever by stimulating
the release of prostaglandins, which act on the temperature control center of
the hypothalamus.
Inflammasomes
IL-1 is synthesized from a larger precursor that is cleaved by a caspase (caspase-1). Caspase-1 is part of two (or more) multi-protein complexes in the cytosol of macrophages and neutrophils that are called inflammasomes. Inflammasomes are activated by several different products produced by invading bacteria. Some of these are first "seen" by toll-like receptors (TLRs) thus providing a link between the innate immune system and inflammation.
Leukotrienes and Prostaglandins
These potent mediators of inflammation are derivatives of arachidonic acid (AA) a 20-carbon unsaturated fatty acid produced from membrane phospholipids.
The principal pathways of arachidonic acid metabolism are
- the 5-lipoxygenase pathway, which produces a collection of leukotrienes (LT)
- and the cyclooxygenase (COX) pathway, which produces prostaglandin H2 (PGH2). PGH2 serves as the substrate for two enzymatic pathways:
- one leading to the production of several prostaglandins (PG);
- the other leading to the production of thromboxanes (Tx).
~The Good Side of Inflammation
The inflammatory response to tissue damage is of great value. By isolating the damaged area, mobilizing effector cells and molecules to the site, and — in the late stages — promoting healing, inflammation protects the body.
Its importance is demonstrated by the problems people with inherited defects in components of the process have with infections.
Some examples:
- a failure to produce reactive oxygen species (ROS) leads to chronic granulomatous disease (CGD)
- inherited defects in the ability to produce the later complement components (C5, C6, C7, C8, C9) increase the risk of certain infections.
~The Bad Side of Inflammation
Often the inflammatory response is out of proportion to the threat it is dealing with. The result can be more damage to the body than the agent itself would have produced.
Allergies and Autoimmune Diseases
All the many types of allergies and many of the autoimmune diseases are examples of inflammation in response to what should have been a harmless, or at least noninfectious, agent.
Some examples:
- Asthma
- Rheumatoid Arthritis (RA)
- Multiple Sclerosis (MS)
- Systemic Lupus Erythematosus (SLE)
- Chronic Obstructive Pulmonary Disease (COPD)
self antigens or persistent antigens from smoldering infections. The antibodies complex with the antigens triggering the complement system with all its mediators of inflammation.The result: immune complex disorders.
Treating Inflammation
Inappropriate inflammation can be treated with:
1. steroids like the glucocorticoid cortisol
2. nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen (e.g., Motrin®, Advil®).
3. a number of proteins produced by recombinant DNA technology.
NonSteroidal Anti-Inflammatory Drugs (NSAIDs)
The NSAIDs achieve their effects by blocking the activity of cyclooxygenase.In addition to reducing the fever and pain of inflammation, NSAIDs also inhibit clotting. They do this by interfering with the synthesis of thromboxane A2 in platelets. This is the reason that
aspirin is given to patients undergoing angioplasty; many men take a baby aspirin a day in the hope of avoiding heart attacks. But regular use of NSAIDs has a downside: a tendency to develop ulcers in the stomach and duodenum.
Enter the COX-2 inhibitors.
COX-1 and COX-2
The body produces several different forms of cyclooxygenase (COX), including
COX-1, which is involved in pain, clotting, and protecting the stomach;Most of the NSAIDs inhibit them both. However, some newer drugs, the so-called COX-2 inhibitors, such as:
COX-2, which is involved in the pain produced by inflammation.
rofecoxib (Vioxx®)are much more active against COX-2 than COX-1. COX-2 inhibitors are effective against inflammation and seem to avoid damage to the GI tract. But, unfortunately, they increase the risk of blood clots — which can cause heart attacks and strokes — because they do not block the synthesis of thromboxane A2 by platelets (which contain only COX-1). So people depending on NSAIDs for their heart protective effects must monitor any use of COX-2 inhibitors carefully.
celecoxib (Celebrex®)
In fact, because of the increased risk of heart attacks and strokes, the manufacturer of Vioxx® removed it from the market on 30 September 2004.
Therapeutic Proteins
Recombinant DNA and monoclonal antibody technology have produced some new therapies that are being enlisted in the battle against damaging inflammation.
- an IL-1 antagonist that binds and inactivates the IL-1 receptor.
etanercept (Embrel®). A soluble version of the TNF-α receptor. It binds TNF-α preventing it from carrying out its many inflammatory actions. Potent but carries a severe risk of allowing infections to develop. - recombinant protein C. To help the body dissolve the tiny clots that are triggered during inflammation.
- infliximab (Remicade®). A monoclonal antibody that binds to TNF-α. Shows
promise against some inflammatory diseases such as rheumatoid arthritis.
(Side-effect: can convert a latent case of tuberculosis into active disease.)
Acute Inflammation: Sepsis and Septic Shock
On occasions, for reasons that are not entirely clear, the inflammatory response — usually to an infection by lipopolysaccharide (LPS)-bearing Gram-negative bacteria — spirals out of control progressing until it involves the entire body. This life-threatening development is called sepsis.
One result is a breakdown in the control of blood clotting. What should have been a mechanism to help wall off an infected area and promote healing leads instead to a dangerous deposition of fibrin in small blood vessels throughout the body. This can lead to septic shock .
a failure of many organs:
- lungs, kidneys, etc.
- a sharp drop in blood pressure and, all too often,
- death
Some Gram-positive cocci can produce a similar condition, but here the eliciting agent is not LPS but a toxin liberated by the bacteria.
In theory, anti-inflammatory agents should be useful in combating sepsis. But so far, only recombinant protein C has shown any promise (by inhibiting the formation of thrombin), and severe bleeding is a dangerous side-effect.
Inflammation and Cancer
Chronic inflammation is also a frequent cause of cancer.
Read more in Bruce Ames's The Causes and Prevention of Cancer
- Liver cancer is often the sequel to years of inflammation caused by
infection by:hepatitis B and/or C viruses. - Lung cancer often is the end stage of years of chronic inflammation caused by inhaled irritants, of which tobacco smoke is the most reliable.
- Cervical cancer can follow chronic infection and inflammation caused by:
- papilloma viruses
- chlamydiae
- Bladder, colon, pancreas, stomach, and other cancers may similarly be the final stage of years of inflammation.
Inflammation and Pancreatitis
Despite the varied causes, the clinical characteristics of acute pancreatitis follow a similar pattern. The severity of the disease and long-term complications may differ, depending on the cause. The primary initiating event, whether traumatic, infectious, or metabolic, is damage to the pancreatic acinar cell by the premature activation of digestive enzymes within the cell. The damaged acinar cell then attracts inflammatory cells and activates platelets and the complement system, which leads to the release of cytokines (such as tumor necrosis factor-alpha, interleukin-1, nitric oxide, and platelet activating factor), free radicals, and other vasoactive substances. These substances damage the gland directly, causing pancreatic edema, ischemia, necrosis, and eventual loss of glandular tissue. Systemically, often within hours of the initial insult, fever, hypotension, tachycardia, hypoxia, and capillary leak syndrome may occur in severe cases. The direct links between these chains of events are not well understood, but current research is targeting this inflammatory cascade for therapy that may be beneficial in all types of pancreatitis, regardless of the inciting event.
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Two Related Links:
Article
http://www.medicinenet.com/script/main/art.asp?articlekey=82463
Inflammatory Genes Raise Lung Cancer Risk
WEDNESDAY, July 11 (HealthDay News) -- Changes in two genes that activate the immune system after tissue damage may increase lung cancer risk, researchers report.
The changes were found on the genes for interleukin 1A and 1B, two molecules that immune system cells secrete in response to infection or tissue damage. The changes may cause the body to overproduce the molecules, which could sustain the inflammatory effects of the damage.
Writing in the July issue of Cancer Research, the researchers observed a stronger effect of the genes in heavy tobacco smokers.
"Our findings help explain how heavy smoking, for example, combines with a genetic predisposition to create a besieged environment within the lungs," lead author Dr. Eric Engels, researcher at the Viral Epidemiology Branch of the U.S. National Cancer Institute's Division of Cancer Epidemiology and Genetics, said in a prepared statement. "Essentially, sustained inflammation alters the microenvironment of the lung tissue, damaging cells and altering DNA."
The study is the first to pinpoint the mechanism by which damage to the lung might cause an inflammatory response from the immune system, leading to cancer. Inflammation is a normal part of the immune system's response to the effects of infection and cell damage, but the researchers argue that prolonged inflammation could increase the risk of lung cancer.
The team examined differences in genes related to inflammation among more than 1,500 lung cancer patients and 1,700 healthy adults. More than 80 percent of the lung cancer patients were former or current smokers.
The researchers then analyzed 59 variations on 37 inflammation-related genes. They found variants in the genes for interleukin 1A and 1B more frequently in patients with lung cancer, especially among heavy smokers.
More Americans die from lung cancer each year than any other type of cancer. In 2003, the most recent year for which data is available, 105,508 men and 84,789 women were diagnosed with lung cancer, while 89,906 men and 68,084 women died from the disease.
-- Madeline Vann
SOURCE: American Association for Cancer Research, news release, July 3, 2007
Copyright © 2007 ScoutNews, LLC. All rights reserved.
Experts uncover clue in rosacea progress By RANDOLPH E. SCHMID, AP Science Writer
Sun Aug 5, 1:23 PM ET
WASHINGTON - Their cheeks glow red for no apparent reason, the condition comes and goes and can worsen over time. It is almost like acne, but generally affects people age 30 to 60.
Researchers now believe they have found a key mechanism that drives rosacea, a possible clue that could point the way to a future treatment for the condition that affects 14 million people in the United States.
Overproduction of two inflammatory proteins results in excessive levels of a third protein that leads to rosacea symptoms, a research team reported in Sunday's online edition of the journal Nature Medicine.
The team found that small proteins called anti-microbial peptides caused the same skin symptoms that are seen in rosacea. The peptides are part of the body's immune system.
"When we then looked at patients with the disease, every one of them had far more peptides than normal," Dr. Richard L. Gallo, chief of the division of dermatology at the University of California, San Diego School of Medicine, said in a statement.
Gallo, who led the research team, also is part of the dermatology section of the Veterans Affairs' San Diego Healthcare System.
A precursor form of these peptides known as cathelicidin normally helps protect the skin from infection. Indeed, some skin problems occur when there is too little cathelicidin.
But it turned out that people with rosacea had too much cathelicidin, and it was different from the form in people without the illness.
Rosacea patients also had high levels of stratum corneum tryptic enzymes (SCTE), the precursor of the disease-causing peptide.
"Too much SCTE and too much cathelicidin leads to the abnormal peptides that cause the symptoms of this disease," said Gallo.
To Dr. Jonathan Wilkin, head of the National Rosacea Society medical advisory board, "It's not that he's gone all the way back and discovered what the cause (of rosacea) is, but the role of cathelicidin in the engine that makes rosacea progressive, that is key."
That finding gives the option for testing to see if there are targets that can reduce the inflammation, Wilkin said in a telephone interview. That may suggest targets for an eventual drug therapy.
Antibiotics sometimes have been used to treat rosacea on the theory it might be caused by bacteria.
Antibiotics tend to alleviate the symptoms of rosacea in patients because some of them work to inhibit these enzymes, Gallo said. "Our findings may modify the therapeutic approach to treating rosacea, since bacteria aren't the right target."
Wilkin, who was not part of the research team, noted that the most effective antibiotics have been those that also have anti-inflammatory effects.
Gallo's research was funded by the National Institutes of Health, the Rosacea Society and the Association for Preventive Medicine of Japan.
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On the Net:
Nature Medicine:
http://www.nature.com/naturemedicine
National Rosacea Society:
http://www.rosacea.org/
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