Transcript Inflammation and metabolism syndrom

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
treatment of acute inflammation）
 chronic inflammation
（lasts weeks, months or even
indefinitely 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 cellmatrix 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 Blymphocytes. 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.
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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 factor
prostacyclin
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 insulinsensitizing 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.
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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.