inflammation part (2)
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NS 521 - Inflammation
• Overview of Cellular Mechanisms Involved in Acute Inflammation
• Chemical Mediators of Acute Inflammation• Examples of Acute Inflammatory Responses• Differences Between Acute and Chronic
Inflammation• Examples of Chronic Inflammation• Discussion of Potential Roles of Nutrition in
Inflammation
Acute InflammationAcute inflammation is a rapid response to an
injurious agent that serves to deliver mediators of host defense—leukocytes and plasma proteins—to
the site of injury. Acute inflammation has three
major components: (1) alterations in vascular caliber that lead to an increase in blood flow; (2) structural changes in the microvasculature that
permit plasma proteins and leukocytes to leave the circulation; and (3) emigration of the leukocytes
from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the
offending agent
Acute inflammatory reactions are triggered by a variety of stimuli:
• Infections (bacterial, viral, parasitic) and microbial toxins
• Trauma (blunt and penetrating) • Physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation;
some environmental chemicals) • Tissue necrosis (from any cause)
• Foreign bodies (splinters, dirt, sutures)
• Immune reactions (also called hypersensitivity reactions)
Acute Inflammation
When a host encounters an injurious agent, such as an infectious microbe or dead cells, phagocytes that reside in all tissues try to get rid of these agents. At
the same time, phagocytes and other host cells react to the presence of the foreign or abnormal substance
by liberating cytokines, lipid messengers, and the
various other mediators of inflammation. Some of
these mediators act on endothelial cells in the vicinity and promote the efflux of plasma and the recruitment
of circulating leukocytes to the site where the offending agent is located.
Acute Inflammation - continued
As the injurious agent is eliminated and anti-inflammatory mechanisms become active, the
process subsides and the host returns to a normal state of health. If the injurious agent cannot be quickly eliminated, the result may be chronic inflammation. The recruited leukocytes are
activated by the injurious agent and by locally produced mediators, and the activated leukocytes
try to remove the offending agent by phagocytosis.
Lymphocyte and Neutrophil Monocyte
The vascular phenomena of acute inflammation are characterized by increased blood flow to the injured
area, resulting mainly from arteriolar dilation and opening of capillary beds induced by mediators such
as histamine. Increased vascular permeability results in the accumulation of protein-rich extravascular fluid, which forms the exudate. Plasma proteins leave the
vessels, most commonly through widened interendothelial cell junctions of the venules. The
redness (rubor), warmth (calor), and swelling (tumor) of acute inflammation are caused by the increased blood
flow and edema.
Circulating leukocytes, initially predominantly neutrophils, adhere to the endothelium via
adhesion molecules, transmigrate across the endothelium, and migrate to the site of injury under the influence of chemotactic agents.
Leukocytes that are activated by the offending agent and by endogenous mediators may release toxic metabolites and proteases
extracellularly, causing tissue damage. During the damage, and in part as a result of the
liberation of prostaglandins, neuropeptides, and cytokines, one of the local symptoms is pain
(dolor).
Changes in vascular flow and caliber begin early after injury and develop at varying rates depending on the severity of the injury.
The changes occur in the following order:
• Vasodilation. Increased blood flow is the cause of the heat and the redness. Vasodilation is induced by the action of several
mediators, notably histamine and nitric oxide on smooth muscle. • Increased permeability of the microvasculature.
• Stasis. The loss of fluid results in concentration of red cells in small vessels and increased viscosity of the blood.
A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich fluid (exudate) into the extravascular
tissue. The loss of protein from the plasma reduces the intravascular osmotic pressure and increases the osmotic pressure of the interstitial fluid. Together with
the increased hydrostatic pressure owing to increased blood flow through the dilated vessels, this
leads to a marked outflow of fluid and its accumulation in the interstitial tissue. The net
increase of extravascular fluid results in edema.
Vascular Permeability – Leakage of Carbon Particles
EDEMA
In acute inflammation, fluid loss from vessels with increased permeability occurs in distinct phases: (1)
an immediate transient response lasting for 30 minutes or less, mediated mainly by the actions of histamine and leukotrienes on endothelium; (2) a delayed response starting at about 2 hours and lasting for about 8 hours, mediated by kinins,
complement products, and other factors; and (3) a prolonged response that is most noticeable after
direct endothelial injury, for example, after burns.
The sequence of events in the journey of leukocytes from the vessel lumen to the interstitial tissue, called
extravasation, can be divided into the following steps:
1. In the lumen: margination, rolling, and adhesion to endothelium. Vascular endothelium normally does not bind circulating cells or impede their passage. In inflammation, the endothelium has to be activated to permit it to bind leukocytes, as a prelude to their exit
from the blood vessels. 2. Transmigration across the endothelium (also
called diapedesis) 3. Migration in interstitial tissues toward a
chemotactic stimulus
Leukocytes Rolling Within a Venule
Neutrophil Pavementing (lining the venule)
Leukocyte Margination and Diapedesis
Neutrophil Transendothelial Migration (Diapedesis)
Table 3–2. Mediators of Acute Inflammation.
Mediator Vasodilation Immediate Sustained Chemotaxis Opsonin Pain
Histamine + +++ – – – –
Serotonin (5–HT) + + – – – –
Bradykinin + + – – – ++
Complement 3a – + – – – –
Complement 3b – – – – +++ –
Complement 5a – + – +++ – –
Prostaglandins +++ + +? – –
Leukotrienes – +++ +? +++ – –
Lysosomal proteases – – ++1
– – –
Oxygen radicals – – ++1
– – –
Resolution of Acute Inflammation
Table 3–4. Types of Acute Inflammation.
Type Features Common Causes
Classic type Hyperemia; exudation with fibrin and neutrophils; neutrophil leukocytosis in blood.
Bacterial infections; response to cell necrosis of any cause.
Acute inflammation without neutrophils
Paucity of neutrophils in exudate; lymphocytes and plasma cells predominant; neutropenia, lymphocytosis in blood.
Viral and rickettsial infections (immune response contributes).
Allergic acute inflammation
Marked edema and numerous eosinophils; eosinophilia in blood.
Certain hypersensitivity immune reactions
Serous inflammation (inflammation in body cavities)
Marked fluid exudation. Burns; many bacterial infections.
Catarrhal inflammation (inflammation of mucous membranes)
Marked secretion of mucus. Infections, eg, common cold (rhinovirus); allergy (eg, hay fever).
Fibrinous inflammation
Excess fibrin formation. Many virulent bacterial infections.
Necrotizing inflammation, hemorrhagic inflammation
Marked tissue necrosis and hemorrhage. Highly virulent organisms (bacterial, viral, fungal), eg, plague (Yersinia pestis), anthrax (Bacillus anthracis), herpes simplex encephalitis, mucormycosis.
Membranous (pseudomembranous) inflammation
Necrotizing inflammation involving mucous membranes. The necrotic mucosa and inflammatory exudate form an adherent membrane on the mucosal surface.
Toxigenic bacteria, eg, diphtheria bacillus (Corynebacterium diphtheriae) and Clostridium difficile.
Suppurative (purulent) inflammation
Exaggerated neutrophil response and liquefactive necrosis of parenchymal cells; pus formation. Marked neutrophil leukocytosis in blood.
Pyogenic bacteria, eg, staphylococci, streptococci, gram–negative bacilli, anaerobes.
Inflammed Lung
Suppurative or purulent inflammation is characterized by the production of large amounts
of pus or purulent exudate consisting of
neutrophils, necrotic cells, and edema fluid.
Serous inflammation is marked by the
outpouring of a thin fluid that, depending on the size of injury, is derived from either the plasma or
the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities (called
effusion).
FIBRINOUS INFLAMMATIONWith more severe injuries and the resulting greater
vascular permeability, larger molecules such as fibrinogen pass the vascular barrier, and fibrin is formed and deposited in the extracellular space
An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflammatory necrotic
tissue
Viral Hepatitis
Chronic InflammationAlthough difficult to define precisely, chronic
inflammation is considered to be inflammation of prolonged duration (weeks or months) in which active
inflammation, tissue destruction, and attempts at repair are proceeding simultaneously. Although it may
follow acute inflammation, chronic inflammation frequently begins insidiously, as a low-grade,
smoldering, often asymptomatic response. This latter type of chronic inflammation is the cause of tissue
damage in some of the most common and disabling human diseases, such as rheumatoid arthritis,
atherosclerosis, tuberculosis, and chronic lung diseases.
Chronic inflammation arises in the following settings:
• Persistent infections
• Prolonged exposure to potentially toxic agents, either exogenous or
endogenous
• Autoimmunity
In contrast to acute inflammation, which is manifested by vascular changes, edema, and predominantly neutrophilic infiltration, chronic
inflammation is characterized by:
• Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells. • Tissue destruction, induced by the persistent offending agent or by the inflammatory cells.
• Attempts at healing by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels (angiogenesis)
and, in particular, fibrosis
Table 5–1. Differences between Acute and Chronic Inflammation.
Acute Chronic
Duration Short (days) Long (weeks to months)
Onset Acute Insidious
Specificity Nonspecific Specific (where immune response is activated)
Inflammatory cells Neutrophils, macrophages Lymphocytes, plasma cells, macrophages, fibroblasts
Vascular changes Active vasodilation, increased permeability New vessel formation (granulation tissue)
Fluid exudation and edema + –
Cardinal clinical signs (redness, heat, swelling, pain)
+ –
Tissue necrosis– (Usually) + (Suppurative and necrotizing inflammation)
+ (ongoing)
Fibrosis (collagen deposition) – +
Operative host responses Plasma factors: complement, immunoglobulins, properdin, etc; neutrophils, nonimmune phagocytosis
Immune response, phagocytosis, repair
Systemic manifestations Fever, often high Low–grade fever, weight loss, anemia
Changes in peripheral blood Neutrophil leukocytosis; lymphocytosis (in viral infections) Frequently none; variable leukocyte changes, increased plasma immunoglobulin
The products of activated macrophages serve to eliminate
injurious agents such as microbes and to initiate the process of repair, and are responsible for much of the
tissue injury in chronic inflammation.
Tissue destruction is one of the hallmarks of chronic inflammation.
In short-lived inflammation, if the irritant is eliminated, macrophages eventually disappear (either dying
off or making their way into the lymphatics and lymph nodes). In
chronic inflammation, macrophage accumulation persists, and is
mediated by different mechanisms
A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of
macrophages that are transformed into epithelium-like cells surrounded by a collar of
mononuclear leukocytes, principally lymphocytes and occasionally
plasma cells.
Table 5–2. Common Causes of Epithelioid Cell Granulomas.
Disease Antigen Caseous Necrosis
Immunologic response
Tuberculosis Mycobacterium tuberculosis ++
Leprosy (tuberculoid type) Mycobacterium leprae –
Histoplasmosis Histoplasma capsulatum ++
Coccidioidomycosis Coccidioides immitis ++
Q fever Coxiella burnetii (rickettsial organism) –
Brucellosis Brucella species –
Syphilis Treponema pallidum ++1
Sarcoidosis2
Unknown –
Crohn's disease2
Unknown –
Berylliosis3
Beryllium (? +protein) –
Nonimmunologic response
Foreign body (eg, in intravenous drug abuse) Talc, fibers (? +protein) –
Lung Granuloma From Tuberculosis (Tubercle)
Vacuolated Macrophages in Leprosy
Foreign Body Granuloma
Scar Formation From a Granuloma
Potential Roles of Nutrition in Inflammation and Immunity
Under-nutritionDeficencies
Protein/CalorieEssential Fatty AcidsZinc, Copper, and IronVitamin AAntioxidantsOther Micronutrients
Over-nutritionObesity
Adipokines
Omega-6 Fatty AcidsEicosinoids
Dietary restriction impairs neutrophil exudation by reducing
CD11b/CD18 expression and chemokine production.
Ikeda, S., et al.Arch Surg. 2001 Mar;136(3):297-
304
Copyright restrictions may apply.
Ikeda, S. et al. Arch Surg 2001;136:297-304.
Circulating polymorphonuclear neutrophil (PMN) kinetics
Copyright restrictions may apply.
Ikeda, S. et al. Arch Surg 2001;136:297-304.
Exudative polymorphonuclear neutrophil (PMN) kinetics
Copyright restrictions may apply.
Ikeda, S. et al. Arch Surg 2001;136:297-304.
Correlation between CD18 expression on circulating polymorphonuclear neutrophils (PMNs) and number of exudative PMNs
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