Local inflammatory responses

Summary

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 local inflammation

  • 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:
    1. Local hemodynamic changes (vasoconstrictionvasodilation)
    2. Increase in vascular permeability
    3. Extravasation of leukocytes
    4. Phagocytosis and killing of the phagocytosed pathogen or lysis of the phagocytosed particles
    5. Outcome of inflammatory response

References: [1][2]

Classic signs of inflammation

Sign Mechanism Mediators
Rubor (redness)
  • Release of vasoactive mediators by immune cells and endotheliumvasodilation↑ blood flow
Calor (heat)
Tumor (swelling)
  • Release of mediators from immune cells and endothelium or damage to endotheliumseparation of endothelial junctions → separation of endothelial cells → ↑ vascular permeability and ↑ paracellular movement of fluid → leakage of protein-rich fluid to the interstitial tissue → ↑ oncotic tissue in the interstitium accumulation of fluid in the interstitium
Dolor (pain)
  • Stimulation of free nerve endings by certain mediators and H+
  • Prolonged stimulation → sensitization of ion channels (e.g., TRPV1) → hyperalgesia
Functio laesa (loss of function)
  • Caused by the combined effect of other cardinal signs

References: [1][3][4]

Local hemodynamic changes

  • Initial transient reflectory vasoconstriction followed by vasodilation
  • Vasodilation is induced by release of inflammatory mediators:
Mediator Source
Histamine Basophils, platelets, mast cells
Serotonin Platelets
Prostaglandins (PGE2, PGD2, and PGF2) Leukocytes, platelets, endothelial cells
Bradykinin Plasma
NO Endothelial cells
  • Due to increased diameter of vessels and leakage of protein-rich fluid into the interstitial tissue (see increase of vascular permeability below), blood stasis occurs, which allows for margination of leukocytes.

References: [1][#377

Increase in vascular permeability

  • Mechanisms
    • Retraction of endothelial cells
      • Due to the action of inflammatory mediators (histamine, serotonin, bradykinin, leukotrienes C4, D4, and T4)
      • Occurs rapidly and does not last long
      • Results in opening of interendothelial spaces and paracellular leakage of plasma
    • Endothelial injury
      • Results in endothelial cell necrosis and detachment
      • Leakage lasts until the damaged area is thrombosed or repaired.
  • Effects
    • Leads to leakage of plasma content into the interstitial tissue
    • Allows migration of immune cells and proteins to site of injury or infection

References: [1][5]

Chemotaxis and leukocyte extravasation

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.

Margination

Rolling

  • 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
      • P-selectin: stored and released from Weibel-Palade bodies within the endothelium in response to inflammation
      • E-selectin: released in response to inflammatory mediators, such as TNF and IL-1
      • Other: GlyCAM-1, CD34
    • On leukocytes

Leukocyte adhesion deficiency type 2 results from errors in rolling due to deficiency of Sialyl-LewisX.

Leukocyte adhesion

Leukocyte adhesion deficiency type 1 results from errors in adhesion due to deficiency of CD18.

Diapedesis

Migration

Cell adhesion molecules involved in leukocyte extravasation

Endothelial cells Leukocytes Notes
Selectins
P-selectin Sialyl-LewisX & PSGL-1
E-selectin Sialyl-LewisX & PSGL-1
GlyCam-1/CD34 L-selectin
Integrins
ICAM-1 LFA-1 (CD18 and CD11a) & MAC-1
VCAM-1 VLA-4

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: [7][6][2]

Phagocytosis and killing

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
Phagocyte receptor Ligand
Mannose receptor Mannose, fucose, N-acetylglucosamine
Scavenger receptor Low-density lipoprotein
Opsonin receptor Fc fragment of IgG, C3b

References: [1][2]

Outcomes of acute inflammation

Outcome Description Associated mediators and cytokines
Resolution with regeneration
Resolution with scarring
  • Cellular debris, pathogens, and edema are cleared.
  • There is a lack of stem cells to replace the damaged tissues → Original tissue is replaced by fibrotic scar tissue.
Abscess formation
  • IL-1β
  • TNF
Chronic inflammation
  • Persistence of causative factor → antigen presentation to T-helper cells → activation of CD4+ Th cells → infiltration of affected tissues

References: [1][5][3]

Chronic local inflammation

Chronic local inflammation is due to nondegradable pathogens, prolonged exposure to toxic pathogens, or autoimmune reactions.

References: [2][1]

Granulomatous inflammation

Granulomatous inflammation is a distinct type of chronic inflammation that is characterized by the formation of granulomas 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.

Etiology

Pathophysiology

Histology

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!

References:[1][8][4][3][9][7]

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  • 7. Zhang H, Sun C, Glogauer M, Bokoch GM. Human Neutrophils Coordinate Chemotaxis by Differential Activation of Rac1 and Rac2. J Immunol. 2009; 183(4): pp. 2718–2728. doi: 10.4049/jimmunol.0900849.
  • 8. Yeldandi AV. Pathology of Pulmonary Infectious Granulomas . In: Pathology of Pulmonary Infectious Granulomas . New York, NY: WebMD. http://emedicine.medscape.com/article/2078678-overview. Updated January 28, 2016. Accessed February 21, 2017.
  • 9. McDonald B, Kubes P. Chemokines: sirens of neutrophil recruitment—but is it just one song?. Immunity. 2010; 33(2): pp. 148–149. doi: 10.1016/j.immuni.2010.08.006.
last updated 12/02/2019
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