28. Vascular and cellular mechanisms and mediators of acute inflammation – greek.doctor (2022)

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Page created on November 12, 2018. Last updated on November 15, 2020 at 12:51

Inflammation in general

Inflammation is the body’s protective response to remove the cause of cell injuries as well as eliminating damaged cells, necrotic cells and initiating regeneration.

The response involves host cells, blood vessels, proteins and other mediators.

What can cause inflammation? Some examples are:

  • Infections
    • Like common cold and pneumonia
  • Allergies
    • Hay fever and asthma
  • Autoimmunity
    • Thyroiditis, vasculitis and glomerulonephritis
  • Chemical damage
    • Alcoholic gastritis and hepatitis
  • Physical damage
    • Burn and radiation
    • Heavy workout leading to repair of overused muscle fibres, and this makes you sore!

Inflammation plays also a role in diseases such as atherosclerosis, Alzheimer’s, prostate hyperplasia and malignant neoplasms.

Acute inflammation

An acute inflammation takes place minutes to hours after the “injury” and the cells involved are mostly neutrophil granulocytes. This leads to vascular changes like vasodilation and increased permeability, as well as increased adhesion and migration of leukocytes caused by activated endothelial cells. Let’s look at the changes in detail.

(Video) Acute Inflammation- Educational 3D Animation

Vascular changes

At first, there will be a very short vasoconstriction due to axon reflexes activated by the sympathetic system when there is something damaging the tissue. Later, the release of histamine, NO and prostaglandins (PGI2) will cause arteriolar vasodilation. This vasodilation will result in hyperaemia, where the active hyperaemia causes increased arterial perfusion, while it passively gives congestion of the capillaries since the venous drainage is decreased.

The permeability of the vessels increases as well, giving leukocytes the opportunity to get to the site of inflammation. There are three responses causing increased permeability:

1. Immediate, transient response

The endothelium in postcapillary venules contract, caused by histamine, bradykinin and leukotrienes. When the endothelial cells contract will they open small spaces between themselves that allow cells to pass through.

This takes place within seconds and up to 15-10 minutes.

2. Immediate sustained response

The endothelial cells will suffer necrosis in arterioles, capillaries and venules at the site of the injury, where the cause for this is the direct injury.

This also happens within seconds but lasts for 4-6 hours.

3. Delayed, prolonged response

The endothelium of venules and capillaries will have cytoskeleton reorganisation and can undergo endothelial apoptosis. This happens 2-12 hours after injury and can last for hours or days.

Leukocyte-mediated endothelial damage can also increase permeability.

(Video) Inflammation Part 1 (HD)

The increased permeability will lead to inflammatory oedema, where protein-rich fluid (exudate) suddenly can flow out of the vessels and will accumulate in the interstitial space.

The lymphatic vessels will also contribute in the inflammatory response. Lymph flow will be increased and helps drain oedema fluid, leukocytes and cell debris from the extracellular space. However, in severe inflammation, especially due to microbes, the lymphatics may transport the pathogens and become secondarily inflamed, a condition called lymphangitis. The draining lymph nodes can also get enlarged due to hyperplasia of lymphoid follicles.

Cellular events of acute inflammation

As you remember from physiology 1 and immunology, we’ve got a lot of different leukocytes in our body. In acute inflammations, the most important cell will be the neutrophil granulocyte, as it’s the most abundant leukocyte in our blood and therefore the first to accumulate.

28. Vascular and cellular mechanisms and mediators of acute inflammation – greek.doctor (1)

The neutrophil granulocyte has the following functions

  • Phagocytosis
  • Produces cytokines
  • Produces antimicrobial agents

The first step is to recognize the potentially harmful agents, and this is done by the molecular pattern recognition, where the receptors on our cells can recognize structures that are common to many pathogens and dead cells. The most important families of these patterns are:

  • Pathogen-associated molecular pattern (PAMP)

We have Toll-like receptors that recognizes e.g. Lipopolysaccharides (LPS) on Gram negative bacteria, endotoxins and flagellin. When the receptors bind to these kind of structures, NF-kB signalling gets activated.

  • Danger-associated molecular pattern (DAMP)

NOD-like receptors will recognize e.g. ATP, uric acid associated proteins and extracellular matrix fragments which are products of dead cells. This leads to activation of inflammasome, a multi-protein cytoplasmic complex which in order activates Caspase-1. Caspase-1 cleaves the precursor of interleukin-1 into interleukin-1 (IL-1).

After the recognition of pathogens or dead cells, leukocytes must be recruited to the site of inflammation.

  • Margination

First, margination will happen, where the leukocytes accumulate at the periphery of the vessels instead of in the centre due to stasis of the blood flow in the capillaries.

  • Rolling

When the endothelial cells are already activated by local mediators and cytokines, they express adhesion molecules, allowing the leukocytes attach loosely to the surface and is able to “roll” on the vessel wall. This mechanism is called rolling, and the adhesion molecules are usually P-selectin and E-selectin.

  • Adhesion

While the leukocyte is rolling on the vessel wall, it will search for integrins to adhere more strongly to the endothelial cells. The endothelial cells will express intercellular adhesion molecule-1 (ICAM1), that binds to Leukocyte function-associated antigen-1 (LFA-1) on the leukocyte, or Vascular cell adhesion molecule-1 (VCAM-1) that binds to integrin very late antigen-4 (VLA-4) on the leukocyte.

(Video) Acute Inflammation - Definition, Pathogenesis, Causes, Mediators, Morphology, Exudate and Transudate

  • Transmigration

After being arrested on the vessel wall, the leukocyte starts to migrate through the vessel wall by squeezing between intercellular junctions. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is expressed on both leukocytes and endothelial cells to mediate the binding events of the leukocyte that are needed to cross the endothelium.

  • Chemotaxis

After escaping the capillaries, the leukocyte moves along a chemical gradient toward the site of infection or injury.

When the leukocyte is at the inflammation site, it will get activated by microbes, products of necrotic cells and mediators. The removal of pathogens by phagocytosis follows these steps:

  • Opsonisation

A type of proteins called opsonins, like the immunoglobulins, coat the surface of microbes and target them for phagocytosis. Leukocytes express receptors that bind to the opsonins, like Fc receptor for IgG (FcγRI), which can bind to IgG.

  • Phagocytosis (engulfment)

The leukocytes’ membrane will zip around the microbe and create a phagosome inside the cell with the ingested microbe.

  • Phagolysosome formation

Phagosome fuses with a lysosome, which contains digestive enzymes, forming a phagolysosome. The lysosomal enzymes digest the contents of the phagolysosome.

  • Chemical killing

Rapid activation of leukocyte NADPH oxidase, also called phagocyte oxidase, converts oxygen into superoxide ion (O2°), which will be converted spontaneously into H2O2. These ROS alone are not enough to kill all microbes, but lysosomes of neutrophils include the enzyme myeloperoxidase that converts H2O2 into hypochlorous radical (HOCl°), that can kill the remaining bacteria successfully.

Nitrogen derived free radicals act in the same way.

Extracellular killing

If the leukocyte fails to phagocytose whatever it wants to phagocytose can the toxic agents be released into the surroundings, which can damage the nearby cells. This is called frustrated phagocytosis. If a neutrophil tries to phagocytose immunocomplexes in the glomerular basement membrane can this happen, as the immunocomplexes are hard to phagocytose.

Some substances, like silica particles, can also rupture the membrane of phagolysosomes and leak the contents into the extracellular space.

(Video) Chronic Inflammation (HD)

Leukocytes also actively secrete granule components like elastase into the extracellular space, that digest and destroy microbes.

Extracellular traps are extracellular fibrillar networks of nuclear chromatin produced by neutrophil and eosinophil granulocytes in response to infectious pathogens, mainly bacteria and fungi. These traps contain antimicrobial substances and prevents spreading of microbes by trapping them. However, this leads to loss of the nuclei and the cell dies.

Mediators of inflammation

The mediators are usually produced at the site of inflammation by the cells there or are produced somewhere else but activated at the site of inflammation. They are tightly regulated and shortly lived.

We distinguish between cell derived mediators and plasma derived mediators.

Cell derived mediators

They are synthetized in response to stimulus and are rapidly secreted when the cell is activated. They are produced by either macrophage, mast cells, endothelial cells and leukocytes at the inflammation site.

Histamine (vasoactive amine)Mast cells, basophils and plateletsVasodilation, increased permeability and endothelial activation
Serotonin (vasoactive amine)PlateletsBoth vasodilation and vasoconstriction, but mostly the former
Prostaglandins (arachidonic acid derivative)Mast cells and leukocytesVasodilation, pain and fever
Leukotrienes (arachidonic acid derivative)Mast cells and leukocytesIncreased permeability, leukocyte adhesion and activation
TNFMacrophages, endothelial cells, dendritic cells, epithelial cellsVasodilation, increased permeability, endothelial activation, decreased contractility of myocardium, cachexia, acute phase reaction
IL-1Macrophages, endothelial cells, dendritic cells, epithelial cellsFever, pain, vasodilation
IL-6T-cell, macrophage, muscle cell, fat cellFever, acute phase reaction
Chemokines (cytokine)Leukocytes and activated macrophagesChemotaxis, leukocyte activation
Platelet activating factor (PAF)Leukocytes and endothelial cellsVasodilation, increased permeability, leukocyte adhesion, chemotaxis, degranulation and oxidative burst.
Nitrogen monoxide (NO)Endothelium and macrophagesVasodilation. Inhibition of both leukocyte-adhesion and platelet aggregation.
Plasma protein derived mediators

These mediators circulate in their inactive form and undergo proteolytic cleavage upon activation at the inflammation site.

ComplementPlasma, but produced in the liverLeukocyte chemotaxis and activation. Direct target killing by MAC. Opsonisation.
KininsPlasma, but produced in liverIncreased permeability, vasodilation, pain.
Thrombin (clotting factor)Plasma, but produced in liverLeukocyte adhesion, PAF production, activation of arachidonate metabolism.
Plasmin (kinin)Plasma, but produced in liverFibrin degradation, C3a conversion.


What are the mediators of acute inflammation? ›

The released chemical mediators include (1) vasoactive amines such as histamine and serotonin, (2) peptide (e.g., bradykinin), and (3) eicosanoids (e.g., thromboxanes, leukotrienes, and prostaglandins).

What is the first vascular event in acute inflammation? ›

When tissue is first injured, the small blood vessels in the damaged area constrict momentarily, a process called vasoconstriction. Following this transient event, which is believed to be of little importance to the inflammatory response, the blood vessels dilate (vasodilation), increasing blood flow into the area.

What are vascular events of acute inflammation? ›

The series of events in the process of inflammation are: Vasodilation: leads to greater blood flow to the area of inflammation, resulting in redness and heat. Vascular permeability: endothelial cells become "leaky" from either direct endothelial cell injury or via chemical mediators.

Which of the following are mediators of inflammation quizlet? ›

TNF and IL1 are major mediators of inflammation. Key actions include: endothelial activation (adhesion molecules, cytokines, chemokines, eicosanoids, GFs, NO), trigger matrix remodeling, systemic acute phase response.

Which mediator is involved in vascular and systemic reaction of inflammation? ›

Prostaglandins • Produced by mast cells , macrophages, endothelial cells, . it involved in vascular and systemic reactions of inflammation.

What is the source of the mediators of inflammation? ›

Sources of inflammatory mediators

Inflammatory mediators important in OM are produced by infiltrating immune cells such as neutrophils, monocytes, and lymphocytes. In addition, local cells such as keratinocytes and mast cells have been shown to produce inflammatory mediators.

What are the three major components of acute inflammation? ›

The main components of the acute inflammatory response are cytokines, acute-phase proteins and leukocytes.

What triggers acute inflammation? ›

Acute inflammation starts after a specific injury that will cause soluble mediators like cytokines, acute phase proteins, and chemokines to promote the migration of neutrophils and macrophages to the area of inflammation.

Which cells are involved in acute inflammation? ›

Cellular Phase. The predominant cell of acute inflammation is the neutrophil. They are attracted to the site of injury by the presence of chemotaxins, the mediators released into the blood immediately after the insult.

What is the mechanism of inflammation? ›

MECHANISMS OF INFLAMMATION. Inflammation consists of a tightly regulated cascade of immunological, physiological, and behavioral processes that are orchestrated by soluble immune signaling molecules called cytokines. The first step of the inflammatory cascade involves recognition of infection or damage (Figure 1b).

What are the 4 stages of inflammation? ›

The four cardinal signs of inflammation are swelling, pain, redness, and localized heat. Sometimes, loss of function is also evident.

What causes vascular permeability in acute inflammation? ›

An increase in blood flow, e.g. as a consequence of vasodilation (34,35), will increase vascular permeability. Molecular regulators of vascular permeability include growth factors and inflammatory cytokines.

Which cytokines are anti inflammatory mediators? ›

Major anti-inflammatory cytokines include interleukin (IL)-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13. Leukemia inhibitory factor, interferon-alpha, IL-6, and transforming growth factor (TGF)-β are categorized as either anti-inflammatory or pro-inflammatory cytokines, under various circumstances.

What cells are considered the body's chemical mediators? ›

Bradykinin is also a major mediator involved in the pain response. Other mediators are derived from injured tissue cells or leukocytes recruited to the site of inflammation. Mast cells, platelets, and basophils produce the vasoactive amines serotonin and histamine.

Which of the following plasma derived mediators of inflammation cause vasodilation? ›

Chemical mediators of inflammation
Vasoactive amines
C5aVasodilation Increased vascular permeability Leukocyte activation and chemotaxis
Arachadonic acid metabolites
ProstaglandinsVasodilation Pain
20 more rows

Which chemical mediator released by damaged tissue and mast cells causes the capillaries to dilate and become more permeable? ›

Injured tissue mast cells release histamine, causing the surrounding blood vessels to dilate and increase in permeability.

Which chemical mediator is primarily responsible for the pain response? ›

The most important kinin is bradykinin, which increases vascular permeability and vasodilation and, importantly, activates phospholipase A2 (PLA2) to liberate arachidonic acid (AA). Bradykinin is also a major mediator involved in the pain response.

Which cells and cell mediators are involved in inflammation? ›

The inflammatory response involves a highly coordinated network of many cell types. Activated macrophages, monocytes, and other cells mediate local responses to tissue damage and infection.

What chemical is responsible for inflammation? ›

The inflammatory response (inflammation) occurs when tissues are injured by bacteria, trauma, toxins, heat, or any other cause. The damaged cells release chemicals including histamine, bradykinin, and prostaglandins. These chemicals cause blood vessels to leak fluid into the tissues, causing swelling.

Why are inflammatory mediators important? ›

Inflammatory mediators have important biological effects on the heart and are key regulators of cardiomyocyte contractile dysfunction, cardiomyocyte cell death, adverse left ventricular (LV) remodeling, and myocardial fibrosis [70].

What are the major events in acute inflammation and what are their functions? ›

Acute inflammation is characterized by local edema, redness, tenderness and pain, increased temperature, and restricted function. If extensive leukocyte accumulation has occurred, the tissue may become firm and hard (induration).

What are the 5 steps of the inflammatory response? ›

Five cardinal signs characterize this response: pain, heat, redness, swelling, and loss of function.

Which medicine is good for inflammation? ›

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
  • Aspirin (available as a single ingredient known by various brand names such as Bayer® or St. ...
  • Ibuprofen (known by brand names such as Motrin® and Advil®).
  • Naproxen sodium (known by the brand name Aleve®).
Jan 25, 2020

Why do I have so much inflammation in my body? ›

Possible Causes

The most common reasons for chronic inflammation include: Autoimmune disorders, such as lupus, where your body attacks healthy tissue. Exposure to toxins, like pollution or industrial chemicals. Untreated acute inflammation, such as from an infection or injury.

What are the types of inflammation? ›

There are two types of inflammation: acute and chronic.

What are the 7 stages of inflammation? ›

The cardinal signs of inflammation include: pain, heat, redness, swelling, and loss of function. Some of these indicators can be seen here due to an allergic reaction. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin calor, dolor, rubor, tumor, and functio laesa).

Can sugar cause inflammation? ›

Sugar. Unfortunately, sugar is on top of the list of foods that may increase muscle and joint inflammation. Numerous studies suggest that processed sugars release pro-inflammatory substances in the body, causing further inflammation in the joints.

Does coffee cause inflammation? ›

Coffee may help reduce inflammation in most people. However, some people may experience increased inflammation following coffee consumption. If this applies to you, consider reducing your intake.

What does mediators of inflammation mean? ›

Mediators of Inflammation: An Introduction - YouTube

What are the pain mediators? ›

Pain mediators included: adrenocorticotropic hormone (ACTH), glucocorticoids, vasopressin, oxitocin, catecholamines, brain opiods, angiotensin II, endorphin / encephalin, vasoactive intestinal peptide (VIP), substance P, eicosanoids (e.g., prostaglandins, leukotrienes), tissue kininogens (bradykinin), histamine, ...


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