Inflammation

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What is inflammation?A normal response of living tissues to injury. It prepares the tissue for healing and repair.

Ultimate goal is to replace injured tissue

The four principal effects of inflammation rubor, tumor, calor and dolorThose were described nearly 2,000 years ago by the Roman Aulus Cornelius Celsus, more commonly known as Celsus.

Aulus Cornelius Celsus (ca. 25 B.C.-A.D. 45) was the Roman author of the first systematic treatise on medicine. It is the most important historical source for present-day knowledge of Alexandrian and Roman medicine

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Author (A) - Aulus Cornelius Celsus (ca. 25 B.C.-A.D. 45) was the Roman author of the first systematic treatise on medicine. It is the most important historical source for present-day knowledge of Alexandrian and Roman medicineRedness (rubor)An acutely inflamed tissue appears red, due to dilatation of small blood vessels within the damaged area (hyperemia).Swelling (tumor)Swelling results from edema, the accumulation of fluid in the extravascular space as part of the inflammatory fluid.

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Heat (calor) Increase in temperature is readily detected in the skin. It is due to increased blood flow (hyperemia) through the region, resulting in vascular dilation and the delivery of warm blood to the area.Pain (dolor) Pain results partly from the stretching and distortion of tissues due to inflammatory edema.

Rubor, Tumor, Calor and Dolor

Loss of function (functio laesa) Loss of function, a well-known consequence of inflammation, was added by Virchow (1821-1902) to the list of features described in Celsus written work.

Rubor, Tumor, Calor and Dolor

Inflammatory Response

Leukocytosis White blood cell count increased above the normal rangeIt is not a disorder or a disease, but a sign of illness.IL-1 and TNF reach the bone marrow and cause acceleratedrelease of leucocytes into the circulation


Endotoxemia Bacteria enter blood stream & release endotoxinWBC react to the presence of bacteria and release inflammatory substance-excessive cytokine productionEndotoxemia specifically refers to circulating gram-negative bacterial toxic products (LPS). There are some cell wall products released from gram-positive bacteria that can have a similar toxic effect.

FeverFever is a common systemic response to inflammationThe elevation of body temperature is thought to improve the efficiency of leukocyte killing and may also impair the replication of many invading organisms..


Type of InflammationInflammation is divided into Acute and Chronic type..Acute inflammation: The inflammation process which starts immediately is called acute inflammation.Cardinal Signs of acute inflammationRedness (rubor) Swelling (tumor)Heat (calor) Pain (dolor) Loss of function (functio laesa)

Components of acute and chronic inflammation

PAMP tissue serotonin,

Acute inflammation

Main components:Vascular changes Vasodilation Vascular permeability Increased adhesion ofwhite blood cellsCellular events Cellular recruitmentand activation ofneutrophils(polymorphonuclearleukocytes)

Acute inflammation

1. Vasodilation:- The reactions of blood vessels- Alterations in vascular caliber (diameter)- Causes decrease in blood pressure2. Vascular leakage and edema:- The accumulation of fluid and proteins of plasma in theextravascular tissues (interstitium)3. Leukocyte emigration to extravascular tissuesA. Margination and rollingB. Activation and adhesionC. Transmigration

Acute inflammation

1. Vasodilation:

Change in vessel flow NO, histaminevascular smooth musclevasodilationincreased blood flow (heat & redness) Stasis: slowed blood flow, hyperviscosity Margination of circulating leukocytes & endothelialactivation Followed by increased permeability of thevasculature Formation of an early transudate (protein-poor filtrateof plasma) gives way to exudate (protein-rich filtrate)into extracellular tissues

3. Leukocyte emigration

Features of chronic inflammation

Chronic inflammation = long duration Components: Lymphocyte, plasma cell, macrophage (mononuclearcell) infiltration

Acute vs. Chronic inflammation

Diseases with chronic Inflammation

Inflammation and Cancer: A Comparative View, J Vet Intern Med 2012;26:1831, Wallace B. Morrison

The normal end result of inflammation is that any damaged tissue or damaged DNA is repaired, the inflammatory response is quenched, and healing takes place. However, during active inflammation the cellular microenvironment is highly reactive and unstable attributable to the combined effects of the many and abundant reactive oxygen and nitrogen species, cytokines, chemokines, reactive aldehydes, and growth factors that are present.

Most of the literature agrees that the sustained generation of free radicals such as the reactive oxygen specieshydroxyl radical (OH) and superoxide (O2) and thereactive nitrogen species nitric oxide (NO) and peroxynitrite (ONOO)

1.Reactive Oxygen and Nitrogen SpeciesInflammation and Cancer: A Comparative View, J Vet Intern Med 2012;26:1831, Wallace B. Morrison

2.Macrophages

Macrophages in particular are important tumor infiltrating cells that affect tumor growth and metastasis. They are found in 2 different polarization states known as M1 and M2. M1 macrophages produce interleukin 12 and promote tumoricidal responses, The mechanisms governing macrophage polarization are unclear.

Another inducible enzyme with carcinogenic properties thatis active within inflamed and malignant tissues is cyclooxygenase-2 (COX-2).


The mechanism by which inflammation causes cancer can be modeled as consisting of an intrinsic and extrinsic pathway.The intrinsic pathway is activated by oncogene activation and tumor suppressor gene inactivation.An example of this is the inflammatory infiltrate noted in human breast cancer described by Virchow in 1863. The extrinsic pathway is one of inflammation that increases the risk of cancer at certain anatomical sites such as the colon, pancreas, prostate.Many of the signaling pathways involved in inflammation and normal healing also play a dual role in providing survival and proliferative signals to initiated cells that lead to cancer promotion and progression.The Mitogen Activated Protein Kinase (MAPK) pathway also has a well-recognized dual role in cancer development and in inflammation.


MAPK pathway

Science

Inflammation