acute & chronic inflammation

Inflammation

 The collective actions of the innate resistance response, combined with responses from adaptive immunity, culminate in a concentrated effort to remove foreign invaders.

 We have used this theme to follow the chemical and cellular responses to an invader that may breach the physical and mechanical barriers of the host. 

 We now examine how the host responds on a larger scale and over longer time periods. Physiologically, the process is called inflammation, and its function is to bring all the host defenses together in response to injury or infection. 

 Inflammation (Latin, inflammatio, to set on fire) is an important innate defense reaction to tissue injury, such as that caused by a pathogen or wound. Two types of inflammation

 (1)  acute inflammation

 (2) Chronic inflammation

Acute inflammation

• Acute inflammation is the immediate response of the body to injury or cell death.
• cardinal signs of inflammation: redness, warmth , pain, swelling and altered function.
• While often thought to be a negative event, wounds do not heal without inflammation.
• The acute inflammatory response begins when injured tissue cells release chemical signals (chemokines) that activate the inner lining (endothelium) of nearby capillaries.
• Within the capillaries, selectins (a family of cell adhesion molecules) are displayed on the activated endothelial cells.
• These adhesion molecules attract and attach wandering neutrophils to the endothelial cells.This slows the neutrophils and causes them to roll along the endothelium, where they encounter the inflammatory chemicals that act as activating signals.
• These signals activate integrins (adhesion receptors) on the neutrophils.
• The integrins then attach tightly to the selectins,
• causing the neutrophils to stick to the endothelium and stop rolling
• (margination).
• The neutrophils now undergo dramatic shape changes,
• squeeze through the endothelial wall (diapedesis) into the interstitial tissue
• fluid,
• migrate to the site of injury (extravasation),
• Neutrophils and other leukocytes are attracted to the infection site by chemotactic factors, which are also called chemotaxins.
• They include substances released by bacteria, endothelial cells, mast cells, and tissue breakdown products.
• Depending on the severity and nature of tissue damage, other types of leukocytes (e.g., lymphocytes, monocytes, and macrophages) may follow the neutrophils.
• The release of inflammatory mediators from injured tissue cells sets into motion a cascade of events that results in the development of the signs of inflammation.
• One response that ensues is the stimulation of local macrophages and distant liver cells to release antimicrobial and acute-phase proteins, respectively.
• In the local response, these mediators increase the acidity in the surrounding extracellular fluid, which activates the extracellular enzyme kallikrein.
•      Cleavage of kallikrein- releases the smaller peptide bradykinin.
• Bradykinin then binds to receptors on the capillary wall, opening the junctions between cells and allowing fluid, red blood cells, and infection fighting leukocytes to leave the capillary and enter the infected tissue.
• Simultaneously, bradykinin binds to mast cells in the connective tissue associated with most small blood vessels.

This activates mast cells by causing an influx of calcium ions, which leads to degranulation and release of preformed mediators such as histamine

If nerves in the infected area are damaged, they release substance P, which also binds to mast cells, boosting preformed mediator release.

Histamine in turn makes the intercellular junctions in the capillary wall wider so that more fluid, leukocytes, kallikrein, and bradykinin move out, causing swelling or edema.

Bradykinin then binds to nearby capillary cells and stimulates the production of prostaglandins (PGE2 and PGF2) to promote tissue swelling in the infected area.

Prostaglandins also bind to free nerve endings, making them fire and start a pain impulse.

At the same time, liver cells release complement proteins,

the iron-binding glycoprotein lactoferrin, andcollectins.

Activated mast cells also release - arachidonic acid, the product of a reaction catalyzed by phospholipase A2.

Arachidonic acid is metabolized by mast cells to form potent mediators, including

PGE2 and PGF2,

thromboxane,

slow reacting substance (SRS), and

leukotrienes (LTC4 and LTD4).

These mediators play specific roles in the inflammatory response

During acute inflammation, the offending pathogen is neutralized and eliminated by a series of important events:

1. The increase in blood flow and capillary dilation bring into the area more antimicrobial factors and leukocytes that destroy the pathogen.

Dead host cells also release antimicrobial factors.

2. Blood leakage into tissue spaces increases the temperature at that site and further stimulates the inflammatory response and may inhibit microbial growth.

3. A fibrin clot often forms and may limit the spread of the invaders.

4. Phagocytes collect in the inflamed area and phagocytose the pathogen.

In addition, chemicals stimulate the bone marrow to release neutrophils and increase the rate of granulocyte production.

The acute inflammatory response should resolve in days to a few weeks.

Prolonged stimulation of the inflammatory pathways leads to progressive changes in cellular response and outcome, known as chronic inflammation.

Recall that the end result of acute inflammation is tissue healing and repair.

However, continued localized inflammation is detrimental and is called chronic inflammation.

 
Chronic inflammation

The development of chronic inflammation occurs slowly and

characterized by a dense tissue infiltration of lymphocytes and macrophages into the affected site and the formation of new connective tissue,

which usually causes permanent tissue damage.

As cycles of cellular infiltration and resolution continue, degradative enzymes

from macrophages destroy more underlying tissue than is replaced.

Furthermore, if the macrophages and other innate responses are unable to protect the host from ongoing infection, chronic tissue injury, or the persistence of poorly degradable materials (sutures, implants, etc.),

the body attempts to wall off and isolate the site by forming a granuloma

(Latin, granulum, a small particle; Greek, om a, to form).

A granuloma is a well-organized mass of neutrophils, epithelioid macrophages, eosinophils, multinucleated giant cells (two or more cells fused into one large cell), fibroblasts, and collagen.

Together, the cells and extracellular matrix proteins form a spherical mass that can bind calcium and form a recalcitrant nodule, mineralizing the granuloma and making it harder to break down.

Importantly, chronic inflammation can occur as a distinct process without much acute inflammation,

The persistence of bacteria can also stimulate chronic inflammation.

For example, mycobacteria, some of which cause tuberculosis and leprosy, have cell walls with a very high lipid content, making them relatively resistant to phagocytosis and intracellular killing.

Granulomas formed around mycobacteria often calcify and appear on chest X rays, indicating potential tuberculosis.

Of note is the fact that the mycobacterial granuloma keeps the bacteria from spreading throughout the body.

However, as the immune system declines, granuloma integrity fails, releasing the bacteria into the alveoli, where they are coughed up and potentially transmitted to another host, having survived for many years within macrophages.