Inflammation is the response of vascularized tissues to harmful stimuli such as infectious agents, mechanical damage, and chemical irritants. Inflammation has both local and systemic manifestations and can 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 following 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 signs are caused by the sequence of events that is triggered by tissue damage and allows leukocytes to reach the site of damage in order to eliminate the causative factor. This sequence involves changes in local hemodynamics and vessel permeability as well as interaction between leukocytes and 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, which confines the causative agent to the site of the initial acute inflammatory response. Chronic inflammation may last months to years and primarily involves the adaptive immune system.
- Definition: an immediate response to a pathogenic factor (e.g., trauma, necrosis, foreign bodies, infection)
Acute inflammation fulfills the following functions:
- Elimination of pathogenic factor
- Removal of necrotic cells resulting from the initial injury
- Initiation of tissue repair
- Rapid onset (occurs seconds to minutes after an encounter with a causative factor)
- Transient and typically short-lasting; (i.e., resolves in minutes to days, provided it is not caused by an immunological condition)
- Involves the innate immune system (i.e., the response is not as specific as in chronic inflammation)
- Release of inflammatory mediators leads to the five classic signs of inflammation: see “” below.
- Inflammatory reaction itself may be harmful to an individual under the following circumstances:
- Acute inflammation fulfills the following functions:
- Cells of the immune system
- Toll-like receptors
- Inflammasome: cytosolic intracellular multi-protein oligomer of the innate immune system that promotes the initiation of inflammatory responses and induction of pyroptosis (a highly inflammatory form of apoptosis that promotes the maturation, activation, and release of proinflammatory cytokines and pore-forming proteins) 
- Arachidonic acid metabolites
Local hemodynamic changes (vascular response to injury)
- Initial vasoconstriction is followed by vasodilation → stasis and ↑ blood flow
Vasodilation is induced by release of the following inflammatory mediators:
- Histamine from basophils, platelets, mast cells
- Serotonin from platelets
- Prostaglandins (PGE2, PGD2, and PGF2) from leukocytes, platelets, endothelial cells
- Bradykinin; (an inflammatory mediator that increases vascular permeability and causes vascular dilation and bronchoconstriction ) from plasma
- Nitric oxide (NO) from endothelial cells
Increased vascular permeability
- Inflammatory mediators (histamine, serotonin, bradykinin, and leukotrienes C4, D4, and E4) rapidly trigger the retraction of endothelial cells → opening of interendothelial spaces and short-lasting paracellular leakage of plasma
- Endothelial injury → endothelial cell necrosis and detachment → long-lasting leakage until the damaged area is thrombosed or repaired
- Leakage of plasma content → edema and promotion of migration of immune cells and proteins to the site of injury or infection
- Cellular effects
|Possible outcomes of acute inflammation |
|Outcome||Description||Associated mediators and cytokines|
|Persistent acute inflammation|
|Resolution with regeneration|
|Resolution with scarring|
|Abscess formation|| || |
|Signs of inflammation |
|Tumor (swelling)|| |
|Functio laesa (loss of function)|| |
- Within inflamed tissue, leukocytes (mainly neutrophils in early infection) interact with the vascular endothelium and leave the blood vessels (predominantly postcapillary venules) to migrate to the site of infection.
- The process of neutrophil extravasation from the blood to the inflamed tissue occurs in 5 steps:
- Definition: a process by which leukocytes are distributed peripherally along the endothelial surface
Mechanism: The two main mechanisms that allow for margination are rouleaux formation and dilation of post-capillary venules.
- Rouleaux formation
- Dilation of post-capillary venules
- The release of inflammatory mediators results 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. 
- Definition: 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
Mechanism: mediated by adhesion molecules (selectins)
- On endothelial cells
- On leukocytes
- Neutrophils and other leukocytes express Sialyl-LewisX and L-selectin, respectively.
- These molecules transiently bind to and dissociate from endothelial selectins, allowing leukocytes to roll along the vascular wall.
- Deficiency of the adhesion molecule Sialyl-LewisX causes leukocyte adhesion deficiency type 2.
- Definition: the firm binding of leukocytes to endothelium prior to migrating out of the vasculature
Mechanism: mediated by adhesion molecules
- On endothelial cells
- On neutrophils and lymphocytes
Neutrophils: lymphocyte function-associated antigen-1 (LFA-1)
- Belongs to β2-integrin family
- Composed of CD18 and CD11a
- Binds to ICAM
- Lymphocytes and monocytes β1-integrin (also called VLA-4) binds to VCAM
- Expression of integrins is activated by leukotriene B4 (LTB4) and C5a.
- The deficiency of a CD18 integrin subunit causes leukocyte adhesion deficiency type 1.
- Neutrophils: lymphocyte function-associated antigen-1 (LFA-1)
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.
- Definition: the transmigration of leukocytes across endothelial barriers (can occur paracellularly or transcellularly)
- Leukocytes leave the blood vessel by moving between endothelial cells.
- 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), an endothelial cell adhesion molecule (ECAM) on neutrophils, endothelial cells, and platelets
- Definition: the process by which leukocytes travel through the interstitium to the site of inflammation after leaving the blood vessels
- Mechanism: Occurs via chemotaxis, which is mediated by chemoattractants 
Mechanism: Phagocytosis involves 3 sequential steps.
- Recognition of a target
- Degradation or killing of the engulfed particle
- Phagocyte recognition receptors and their ligands
Killing and degradation 
- Involves production of reactive oxygen species (see “ ”)
- There are a number of diseases associated with defective oxygen-dependent killing, including:
- Oxygen-independent: involves lysosomal enzymes such as acidic hydrolases and lysozyme
- Cells involved
- Mononuclear invasion that causes tissue damage on the one hand, but is simultaneously carrying out repair (in form of fibrosis and angiogenesis) on the other
- Interaction of macrophages and T lymphocytes → chronic inflammation
- There are two possible ways of activating macrophages:
- Distinct type of chronic inflammation that is characterized by the formation of in affected tissues
- May be induced by continuous T-cell response
- When the immune system is unable to completely eliminate a foreign stimulus (e.g., persistent pathogen, foreign body, infections such as TB, immune-mediated diseases), the resulting granulomatous inflammation attempts to wall off the foreign substance within granulomas without completely degrading or eradicating it.
- This results in persistent inflammation that ultimately causes organ damage and fibrosis.
- Infections (most common cause)
- (de Quervain)
- Foreign body exposure
- Others: chronic granulomatous disease
- Antigen-presenting cells present antigens to and secrete cells stimulation of →Th cell differentiation into
- Th1 cells activate macrophages by secreting →cytokine release from macrophages (e.g., TNF) → formation of and
- Epithelioid cells secrete TNF-α, which serves to maintain the granuloma.
- Macrophages within the granuloma cause ↑ calcitriol activation due to ↑ 1α-hydroxylase activity → hypercalcemia
Granuloma: a nodular collection of central macrophages, epithelioid cells (a differentiated tissue macrophage characterized by abundant pink cytoplasm), and multinucleated giant cells surrounded by fibroblasts and lymphocytes, which contain the following structures:
- Schaumann bodies: cellular inclusion bodies consisting of intracytoplasmic calcium and protein with laminar stratification (e.g., sarcoidosis, tuberculosis, Crohn disease, berylliosis)
- Asteroid bodies: star-shaped, eosinophilic inclusion bodies consisting of various lipids (e.g., from sarcoidosis, foreign body reactions)
- Types of granuloma
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.