Local inflammatory responses


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)
Calor (heat)
Tumor (swelling)
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

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.

Leukocyte margination

Leukocyte rolling

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.


Leukocyte migration

Cell adhesion molecules involved in leukocyte extravasation

Endothelial cells Leukocytes Notes
P-selectin Sialyl-LewisX & PSGL-1
E-selectin Sialyl-LewisX & PSGL-1
GlyCam-1/CD34 L-selectin
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: [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.

  • Recognition
    • Phagocytes have a number of receptors that allow them to recognize and bind surface molecules of target cells or particles.
    • Opsonization facilitates recognition of target particles.
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.




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!


  • 1. Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. Philadelphia, PA: Elsevier Saunders; 2014.
  • 2. Le T, Bhushan V,‎ Sochat M, Chavda Y, Abrams J, Kalani M, Kallianos K, Vaidyanathan V. First Aid for the USMLE Step 1 2019. New York, NY: McGraw-Hill Medical.
  • 3. Le T, Bhushan V,‎ Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017.
  • 4. Goljan EF. Rapid Review Pathology. Philadelphia, PA: Elsevier Saunders; 2018.
  • 5. Barone J, Castro MA. Kaplan USMLE Step 1 Lecture Notes 2016. New York, NY, USA: Kaplan Medical; 2016.
  • 6. Granger DN, Senchenkova E. Inflammation and the Microcirculation. Anatomical Considerations. 2010: p. Chapter 3. url: https://www.ncbi.nlm.nih.gov/books/NBK53381/.
  • 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.
  • Mariathasan S, Newton K, Monack DM, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004; 430(6996): pp. 213–218. doi: 10.1038/nature02664.
  • Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nature Reviews Immunology. 2016; 16(7): pp. 407–420. doi: 10.1038/nri.2016.58.
last updated 09/02/2020
{{uncollapseSections(['Ac1RUf0', 'zc1rUf0', '_c15Uf0', '-c1DUf0', 'Z11Z2f0', '011e2f0', 'a11Q2f0', 'Y11n2f0', 'b11H2f0', 'X1192f0'])}}