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