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 Inflammation
Acute 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; Bacterial infections; response to cell necrosis of any
neutrophil leukocytosis in blood. cause.

Acute inflammation Paucity of neutrophils in exudate; lymphocytes and Viral and rickettsial infections (immune response
without neutrophils plasma cells predominant; neutropenia, lymphocytosis contributes).
in blood.

Allergic acute Marked edema and numerous eosinophils; eosinophilia Certain hypersensitivity immune reactions
inflammation in blood.

Serous Marked fluid exudation. Burns; many bacterial infections.

inflammation
(inflammation in
body cavities)

Catarrhal Marked secretion of mucus. Infections, eg, common cold (rhinovirus); allergy
inflammation (eg, hay fever).
(inflammation of
mucous
membranes)
Fibrinous Excess fibrin formation. Many virulent bacterial infections.
inflammation
Necrotizing Marked tissue necrosis and hemorrhage. Highly virulent organisms (bacterial, viral, fungal),
inflammation, eg, plague (Yersinia pestis), anthrax (Bacillus
hemorrhagic anthracis), herpes simplex encephalitis,
inflammation mucormycosis. 

Membranous Necrotizing inflammation involving mucous Toxigenic bacteria, eg, diphtheria bacillus
(pseudomembranou membranes. The necrotic mucosa and inflammatory (Corynebacterium diphtheriae) and Clostridium
s) inflammation exudate form an adherent membrane on the mucosal difficile. 
surface.

Suppurative Exaggerated neutrophil response and liquefactive Pyogenic bacteria, eg, staphylococci, streptococci,
(purulent) necrosis of parenchymal cells; pus formation. Marked gram–negative bacilli, anaerobes.
inflammation neutrophil leukocytosis in blood.
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 INFLAMMATION
With 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 Inflammation
Although 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 + (ongoing)

– (Usually)
+ (Suppurative and necrotizing inflammation)

Fibrosis (collagen deposition) – +

Operative host responses Plasma factors: complement, immunoglobulins, properdin, etc; Immune response, phagocytosis, repair
neutrophils, nonimmune phagocytosis

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-nutrition
Deficencies
Protein/Calorie
Essential Fatty Acids
Zinc, Copper, and Iron
Vitamin A
Antioxidants
Other Micronutrients
Over-nutrition
Obesity
Adipokines
Omega-6 Fatty Acids
Eicosinoids
 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
 Circulating polymorphonuclear neutrophil (PMN) kinetics

Ikeda, S. et al. Arch Surg 2001;136:297-304.

Copyright restrictions may apply.

 Exudative polymorphonuclear neutrophil (PMN) kinetics

Ikeda, S. et al. Arch Surg 2001;136:297-304.

Copyright restrictions may apply.

Correlation between CD18 expression on circulating polymorphonuclear neutrophils (PMNs) and
number of exudative PMNs

Ikeda, S. et al. Arch Surg 2001;136:297-304.

Copyright restrictions may apply.