Inflammation and metabolism syndrome

LU YING LI

Ph.D& MD

INFLAMMATION

Inflammation is a normal response of the body to protect tissues from infection, injury or disease.

The inflammatory response begins with the production and release of chemical agents by cells in the infected, injured or diseased tissue.

These agents cause redness, swelling, pain, heat and loss of function.

This inflammatory response usually promotes healing but, if uncontrolled, may become harmful.

Acute inflammation （ typically lasts only a few days. The t

reatment of acute inflammation ）

chronic inflammation （ lasts weeks, months or even indefinit

ely and causes tissue damage ）

CHRONIC INFLAMMATION

In chronic inflammation the inflammation becomes the problem

rather than the solution to infection, injury or disease

Chronically inflamed tissues continue to generate signals that attract leukocytes from the bloodstream. This chronic inflammatory response can break down healthy tissue in a misdirected attempt at repair and healing.

chronic inflammation include, among others:

Atherosclerosis, including coronary artery disease

Atherosclerosis

is the leading cause of morbidity and mortality in Western societies, claiming more lives each year than all forms of cancer combined. Coronary artery disease (CAD) is the most common, and serious, consequence of this disease. Up to 50% of all deaths in the seven major pharmaceutical markets (United States, France, Germany, Italy, Spain, United Kingdom, and Japan) are attributable to CAD.

Atherosclerosis is a common and progressive disease of the arteries that results from inflammation and the buildup of plaque under the inner lining of arteries and swells into the hollow or lumen of the arteries. This accumulation takes place over years, even decades, developing slowly and insidiously. Plaque formation begins as fatty streaks on the inner arterial wall. Over time the fat deposits accumulate and grow, narrowing the opening of the artery. Surrounding smooth muscle tissue also proliferates to form larger plaques. The damage from atherosclerosis occurs when the swelling, called a plaque, becomes large enough to reduce or completely block the blood flow through the arteries. The artery wall becomes thickened and loses its elasticity. Any tissue supplied by the blocked artery is in danger. Risk factors associated with atherosclerosis include: elevated cholesterol and triglyceride levels, high blood pressure, smoking, diabetes mellitus (type 1 diabetes), obesity and physical inactivity. Atherosclerosis, depending on the location of the artery it affects, may result in heart attack, stroke or amputation. Atherosclerosis of the blood vessels of the heart is called coronary artery disease. There are no medications available for physicians to treat directly the underlying chronic inflammation of atherosclerosis.

Many physicians are only now becoming aware of the key role of chronic inflammation in diverse diseases such as atherosclerosis and asthma for which existing anti-inflammatory treatments are incomplete and limited in use. As more physicians recognize that a wide range of chronic diseases are inflammatory in nature, we believe that these physicians will require safer and more effective anti-inflammatory treatments. We believe that one of these therapeutic approaches will be the administration of drugs designed to block the migration of leukocytes through blood vessel walls into inflamed tissues.

As for inflammation, growth factors for wound healing are continually being discovered. "Big Robbins" lists the seven growth factors which seem to direct the production of granulation tissue. You should recognize platelet-derived growth factor as a key to fibroblast activation and fibrogenesis, and recognize the names of the others ("epidermal growth factor", "fibroblast growth factor", "transforming growth factors α and β", interleukin 1, and TNF/cachectin.) Angiogenesis remains rather mysterious; a couple of factors are known (Science 268: 567, 1995).

Fibrin itself seems to attract inflammatory cells, fibroblasts, and angioblasts. Contact inhibition and crowding seem to put the brakes on the process. Material in "Big Robbins" on cell-cell and cell-matrix interactions are still experimental. Now is a good time to read up on "integrins" in your biochemistry book; such medicines as natalizumab (α4 integrin antagonist that has been found to be useful in Crohn's disease and multiple sclerosis) will probably come into use soon.

In clinically significant disease, we believe that the tissue macrophages are almost all recruited directly from the bloodstream monocytes. Plasma cells produce antibodies against the persistent antigen or the altered tissue components. Lymphocytes are likely to be present even where there is no involvement of the immune system.

Plasma cells appear in chronic inflammation as a result of T-helper cells activating B-lymphocytes. Interleukin 1 causes the B-cells to divide. The transformation into plasma cells is mediated (at least in part) by interleukin 4.

Inflammation is said to resolve when no structural cells have been lost after the inflammatory process is complete and phagocytosis has cleaned up the area. When the tissue has been damaged during the inflammatory process or in other ways, but the body itself is still alive, the tissue will either regenerate or be repaired by fibrous tissue. If none of the latter is required, the word "resolution" is also appropriate. If any repair by fibrous tissue occurs, there will be a scar.

A few hours after injury, there is already evidence of connective tissue repair. Fibroblasts become active and begin to proliferate, and buds ("angioblasts") sprout from the damaged capillaries. Of course, the cells will show lots of euchromatin, large nucleoli, and abundant basophilic cytoplasm. Typically, both kinds of cells invade the fibrin meshwork created during the injury and inflammatory response.

The fibroblasts produce ground substance, fibronectin, and type III collagen; later they will produce type I collagen for the mature scar.

The young vessels are leaky, so healing wounds are edematous both grossly and microscopically. The fibroblasts lay down collagen and proteoglycans ("ground substance"), and some acquire contractile elements as in smooth muscle ("myofibroblasts"). Of course, there are plenty of macrophages (to keep the new tissue clean) and mast cells. The new tissue is called granulation tissue ("immature scar", etc.), and the fibrin meshwork is said to be undergoing organization. You've seen granulation tissue -- it was moist, red, jelly-like stuff under the scab that you picked off too soon.

Antibody-Mediated Cytotoxicity

Immediate Hypersensitivities Autoimmune disorders Persistent infections Asthma is a common chronic

inflammatory disease of the bronchial tubes

Transplant Rejection

The familiar symptoms -— lameness, swelling, and heat —- are usually the result of inflammation in the synovial membrane and joint capsule

The inflamed synovial membrane and the leukocytes release destructive enzymes such as free radicals, cytokines, and prostaglandins, all of which are potentially damaging to the articular cartilage.

molecules mediates the effect:bradykinin

C3a C3b C5a histamine IgE interferon interleukin 1 leukotrienes membrane attack complex platelet-derived growth factorprostacyclin prostaglandin E serotonin transforming growth factor β thromboxane A2

Other scientists are seeking to determine if inflammation may be one reason that obesity has been linked to higher cancer risk. Research now suggests that the body 抯 fat cells produce cytokines (proteins that promote low-grade inflammation) and that the distribution of body fat might also play a role.

A study in the Journal of the American Medical Association shows that one measure of inflammation increased by more than 50 percent in obese women whose fat was mainly in their hips and thighs ( 損 ear-shaped?, and by more than 400 percent in obese women with significant waistline fat ( 揳 pple-shaped?.

Lazar and colleagues now view obesity as a state of chronic inflammation and speculate that in obese individuals inflammatory cytokines lead to elevated production of resistin by macrophages and elevated serum resistin levels, which in turn contribute to insulin resistance and diabetes. This is consistent with some studies that have found higher resistin levels in obese individuals and patients with insulin resistance and/or diabetes, but not all studies have found such differences.

This response can be blocked by the thiazolidinedione rosiglitazone and by aspirin, two drugs that have dual anti-inflammatory and insulin-sensitizing actions and antagonize the immune regulator NF-kappaB. The researchers go on to show that activation of NF-kappaB is sufficient to induce resistin expression. And NF-kappaB is necessary for the resistin response to inflammatory stimuli.

Studies in our lab and others have clearly demonstrated that adipocytes produce and regulate many metabolic and hormonal signals, which generate profound effects on systemic endocrine equilibrium. In our earlier studies, we have demonstrated that these cells exhibit an inflammatory capacity which is abnormal in obesity and key to the pathogenesis of insulin resistance and diabetes. Recently, we identified a key molecular mechanism underlying the link between inflammatory responses and insulin action. This pathway involves obesity-related activation of the serine.threonine kinase, JNK, and the consequent inhibition of insulin receptor signaling via phosphorylation of a substrate of insulin receptor, IRS-1. In mice lacking JNK genes, there is dramatic protection from obesity and diabetes. There is also genetic evidence that JNK activation is linked to type 2 diabetes in humans. Currently, we are investigating the detailed molecular mechanisms underlying this crosstalk and explore therapeutic and preventive possibilities for diabetes and obesity by blocking JNK function. We are also broadly pursuing the molecular mechanisms of the crosstalk between inflammatory and metabolic pathways. These studies have recently led to the discovery of endoplasmic reticulum stress as the central mechanism linking metabolic stress with insulin resistance and type 2 diabetes. The mechanisms leading to ER stress and targeting these pathways for novel therapeutic strategies are also being explored.