Inflammation is the response of the body's vascularized tissues to harmful stimuli such as infectious agents, mechanical damage, chemical irritants, etc. Inflammation has both local and systemic manifestations and may be either acute or chronic. Local inflammatory response (local inflammation) occurs within the area affected by the harmful stimulus. Acute local inflammation develops within minutes or hours after the influence of a harmful stimulus, has a short duration, and primarily involves the innate immune system. The five classic signs of acute local inflammation are redness, swelling, heat, pain, and loss of function. These classical signs result from the sequence of events that are triggered by tissue damage and allow leukocytes to get to the site of damage to eliminate the causative factor. This sequence involves changes in local hemodynamics and vessel permeability, as well as a complex interaction of leukocytes with endothelium and interstitial tissue through which leukocytes escape the blood vessels. To sustain the vascular changes and attract more immune cells to the site of inflammation, leukocytes and tissue cells secrete a range of inflammatory mediators including interleukins and chemokines. Elimination of the causative factor by leukocytes leads to the resolution of acute inflammation and tissue repair with complete regeneration or scarring. Failure to eliminate the causative agent or prolonged exposure to the causative agent leads to chronic inflammation. It aims to confine the causative agent, may last months to years and primarily involves the adaptive immune system.
Acute inflammation is an immediate response to a pathogenic factor (e.g., trauma or infection) and has the following features:
- Rapid onset (occurs minutes to hours after an encounter with a causative factor)
- Transient and typically short-lasting (provided it is not caused by an immunological condition)
- Involves the innate immune system
- Characterized by five classic signs of inflammation, which are caused by the release of inflammatory mediators
- The sequence of events in inflammatory response include:
|Tumor (swelling)|| |
|Functio laesa (loss of function)|| |
- Initial transient reflectory vasoconstriction followed by vasodilation
- Vasodilation is induced by release of inflammatory mediators:
|Histamine||Basophils, platelets, mast cells|
|Prostaglandins (PGE2, PGD2, and PGF2)||Leukocytes, platelets, endothelial cells|
- Due to increased diameter of vessels and leakage of protein-rich fluid into the interstitial tissue (see below), blood stasis occurs, which allows for margination of leukocytes.
- Retraction of endothelial cells
- Results in endothelial cell necrosis and detachment
- Leakage lasts until the damaged area is thrombosed or repaired.
Within inflamed tissue, leukocytes (mainly neutrophils in early infection) interact with the vascular endothelium and leave the blood vessels to migrate to the site of infection. The process of neutrophil extravasation ; from the blood to the inflamed tissue occurs in 5 steps: margination, rolling, adhesion, diapedesis, and migration.
- A process by which leukocytes are distributed peripherally along the endothelial surface.
The two main mechanisms that allow for margination are rouleaux formation and dilation of post-capillary venules.
- Rouleaux formation
Dilation of post-capillary venules
- Inflammatory mediators result in vasodilation of the post-capillary venules.
- As these venules expand, the velocity of blood flow in these areas slows, causing neutrophils to marginate against the endothelium of the venules.
- The venules are the segment of microvasculature most sensitive to inflammation. Their intercellular endothelial junctions open to allow for the flow of plasma proteins and leukocytes between cells. 
- Rolling is a transient weak interaction of leukocytes with endothelial cells that causes them to move slowly along the blood vessel periphery in areas of inflammation in preparation for adhesion.
- Mediated by the following adhesion molecules:
- On endothelial cells
- On leukocytes
- The firm binding of leukocytes to endothelium prior to migrating out of the vasculature
- Mediated by the following adhesion molecules:
- On endothelial cells
- On neutrophils and lymphocytes
results from errors in adhesion due to deficiency of CD18.
- Movement of leukocytes through the blood vessel wall to the interstitium
- Neutrophils release type IV collagenase, which dissolves the basement membrane and allows them to exit the interstitial space.
- Requires expression of platelet endothelial cell adhesion molecule-1 (PECAM-1, also called CD31) on neutrophils, endothelial cells, and platelets
- The process by which leukocytes move to the cite of inflammation after leaving the blood vessels
- Occurs via chemotaxis, which is mediated by chemoattractants such as: 
Cell adhesion molecules involved in leukocyte extravasation
|P-selectin||Sialyl-LewisX & PSGL-1|
|E-selectin||Sialyl-LewisX & PSGL-1|
|ICAM-1||LFA-1 (CD18 and CD11a) & MAC-1|
To remember the role of different adhesion molecules: Selectins are molecules that allow leukocytes to select the place of their migration (weak binding), while integrins are molecules that integrate (strong binding) the leukocytes with the endothelial cells.References: 
Phagocytosis is the process by which foreign particles, cell debris, or microbes are engulfed and degraded. Cells capable of phagocytosis are called phagocytes (e.g., neutrophils, macrophages). Phagocytosis involves 3 sequential steps: recognition of a target, engulfment, and degradation or killing of the engulfed particle.
|Important phagocyte recognition receptors|
|Mannose receptor||Mannose, fucose, N-acetylglucosamine|
|Scavenger receptor||Low-density lipoprotein|
|Opsonin receptor||Fc fragment of IgG, C3b|
Killing and degradation
- Involves production of reactive oxygen species (see )
- Diseases associated with defective oxygen-dependent killing
- Oxygen-independent: involves lysosomal enzymes such as acidic hydrolases and lysozyme
|Outcome||Description||Associated mediators and cytokines|
|Resolution with regeneration|
|Resolution with scarring|
|Abscess formation|| |
Chronic local inflammation is due to nondegradable pathogens, prolonged exposure to toxic pathogens, or autoimmune reactions.
- Cells involved: mononuclear cells (monocytes, macrophages, lymphocytes, plasma cells), fibroblasts
- Leads to necrosis and fibrosis (simultaneous destruction and formation of new tissue)
- May last for months to years
- Mechanism involves two ways of activating macrophages
Granulomatous inflammation is a distinct type of chronic inflammation that is characterized by the formation of in the affected tissue. If the immune system is unable to completely eliminate a foreign substance (e.g., persistent pathogen, foreign body), the resulting granulomatous inflammation attempts to wall off the foreign substance within granulomas without completely degrading or eradicating it.
- Infections (most common cause)
- (de Quervain)
- Foreign body exposure
- Antigen-presenting cells present antigens to and secrete cells → stimulate differentiation into → Th1 cells activate macrophages by secreting → macrophages release cytokines (e.g., TNF), which stimulates the formation of and
- Macrophages; within the granuloma ↑ calcitriol (1,25-[OH]2 vitamin D3) activation → hypercalcemia
Granuloma: a nodular collection of central macrophages, epithelioid cells, and giant cells, surrounded by fibroblasts and lymphocytes
Giant cells contain:
- Asteroid bodies: a star-shaped, eosinophilic inclusion body consisting of various lipids (e.g., from sarcoidosis, foreign body reactions)
- Schaumann bodies: a type of cellular inclusion body consisting of intracytoplasmic calcium and protein with laminar stratification (e.g., sarcoidosis, tuberculosis, Crohn disease, berylliosis)
- Giant cells contain:
Two types of granuloma
Caseating granulomas: granulomas with central necrosis
- Occurrence: infections (e.g., tuberculosis, fungal infections)
- Non-caseating granulomatous inflammation: granulomas without central necrosis
- Caseating granulomas: granulomas with central necrosis
TNF-α is important for maintaining the granuloma. It is essential to test patients for latent TB before initiating anti-TNF therapy because the drug causes breakdown of the granuloma and can result in disseminated TB!