Vascular endothelial cells forms more than just a passive channel for blood
Before now, scientists believed that vascular endothelium acts only as a passive barrier between blood and tissues and plays no active role in inflammation. However, current knowledge reveals that vascular endothelium and vascular endothelial cells synthesize and release a number of biologically active molecules, which act as potent mediators. Biologically active molecules released by vascular endothelial cells stimulate the evolution of many aspects of inflammatory process including
- vasodilation of local microvessels
- increased vascular permeability
- leukocytes adhesion to endothelial cells and consequent emigration
- healing and fibrosis of inflamed tissue
Vascular endothelial cells, their role in vasodilation of local microvessels
Vascular endothelial cells contribute to regulating and controlling the diameter of blood vessels by releasing relaxing factors and contracting factors when they receive appropriate stimulus. Among the contracting factors released by vascular endothelial cells are endothelin-1, thromboxane A2, prostaglandin H2 and angiotensin-II. Vascular endothelial cells synthesize and release two well-known relaxing factors: nitric oxide (NO) and prostaglandin I2 (prostacyclin). The two relaxing factors synthesized by vascular endothelial cells induce vasodilation of local microvessels.
Both pathogenic and non-pathogenic stimuli can stimulate vascular endothelial cells to produce the relaxing factors. Among the non-pathogenic stimuli that stimulate vascular endothelial cells to produce relaxing factors are chemicals such as leukotriene C, histamine, thrombin, cytokines endotoxins, hypoxia, and direct physical tissue damage. PGI2 (prostacyclin) causes vasodilation by relaxing vascular smooth muscles.
Endothelial cells, their role in leukocyte emigration
The main essence of inflammation is to deliver leukocytes to troubled tissue area. Cytokines and other agents up-regulates the synthesis and expression of cell adhesion molecules by vascular endothelial cells. Besides, leukocytes also increase their expression of cell adhesion molecules. Without the expression of cell adhesion molecules by vascular endothelial cells leukocyte adhesion to vascular endothelial cells will fail to occur.
Endothelial cell adhesion molecules bind to cell adhesion molecules on leukocytes, consequently causing a stable arrest of leukocytes. Following the adhesion of leukocytes to vascular endothelium, leukocytes emigrate from blood vessels to tissues by squeezing through gaps between endothelial cells.
In contrast to neutrophils, which arrive inflammatory sites shortly after the inciting stimulus, monocytes arrive the inflammatory site several hours later. Monocytes, like every other white blood cell circulates in blood vessel normally. However, monocyte emigrate from blood vessels to tissues spaces during inflammation. Like neutrophils, monocytes adhere to activated endothelium, and extravasate into tissue spaces under the influence of chemotaxins and cell adhesion molecules. An important chemotaxin that induces the chemotaxis of monocytes is monocyte chemoattractant protein-1 (MCP-1)
Once monocytes arrive at the tissues, they differentiate into functionally more effective phagocytic cells called macrophages. Monocytes and macrophages are mononuclear cells, and constitute the mononuclear phagocyte system. With phagocytic ability, macrophages are superior to neutrophils. Macrophages can perform many more rounds of phagocytosis and can eat up particle that are too large for neutrophils to engulf. However, it is important to state here that there are microbes which macrophages are unable to engulf.
Macrophages recognize and bind to pathogenic foreign cells by using specific surface receptors called toll-like receptors. Toll-like receptors recognize and bind to pathogen-associated-molecular-patterns (PAMPs) such as lipopolysaccharides and lipoproteins expressed on invading pathogens.
Macrophages, essential in inducing systemic responses to local acute inflammation
Macrophages play crucial roles in most of the systemic responses to acute local inflammation. Particularly, macrophages release cytokines that initiate the processes that leads to the development of systemic effects such as fever and leukocytosis during inflammation. Fever occurs mostly in pathogen-induced inflammation. During an infection, activated macrophages release chemokines and pro-inflammatory cytokines such as IL-1, and TNF-α which diffuse surrounding vessels and flow in blood. When IL-1, and TNF-α get to hypothalamus, they induce the synthesis of inflammatory prostaglandins. PGE2 acts on the hypothalamic thermoregulatory center to reset the set point temperature to a higher value.
In addition, inflammatory cytokines released by macrophages act on hematopoietic stem cells in bone marrow stimulating bone marrow to produce and release more white blood cells into circulation. During severe infections, bone marrow releases even immature white blood cells into circulation. This causes a significant rise in the number of circulating white blood cells; a condition called leukocytosis. Leukocytosis is an important systemic response to inflammation, and macrophages play significant role in leukocytotic response.
Macrophages, particularly release pro-inflammatory cytokines (chemokines inclusive) that attract more neutrophils and other white blood cells to the site of inflammation.
Besides the phagocytosis of invading microbes, macrophages engulf dead cells and tissue debris cleaning up the mess in the inflamed area. The clean up, by macrophages forms part of the tissue healing process.
Mast cells are tissue immune cells. They are particularly abundant in connective tissues, mucosa of GIT, airways, and skin. Mast cells lack phagocytic ability. Mast cells degranulate massively when stimulated appropriately. Degranulation is the release of cytoplasmic contents, which include preformed pro-inflammatory products such as histamine, heparin, IL-5 (eotaxin) and serotonin.
Sensitization of mast cells must occur prior to degranulation
The first time an allergic individual encounters an allergen, the individual’s body system produces IgE antibodies than necessary. IgE molecules attach to their specific receptors on mast cells mainly. Basophils and eosinophils also express surface receptors for IgE. Sensitization is the process where an IgE bind receptors on mast cells for the first time and prepares the mast cell for degranulation if the cognate allergen binds to the mast cell-fixed IgE antibodies. Masts cell fixed IgE antibodies can remain viable weeks, awaiting a second exposure to the same allergen. If this individual has a brush with the same allergen for the second time, the allergens bind to cell-fixed IgE antibodies. The allergen-antibody interaction triggers mast cells to release the content of their granules into the surrounding tissues.
Moreover, mast cells can degranulate if C5a and C3a fragment of complement bind to their receptors on mast cell surface membranes. The pro-inflammatory mediators released by mast cells together cause increased vascular permeability, vasodilation, attraction of eosinophils to the site of reaction, and local tissue destruction.
Mast cells and basophils underpin allergic reactions, and are responsible for the inflammatory component of allergic reactions. Interestingly mast cells express surface receptors for a special class of antibodies, immunoglobulins (Ig) E. Non-allergic individuals produce very little quantity of IgE antibody subtype, whereas allergic individuals produce vast amounts of IgE antibody subtype.
When an allergic person contacts an allergen for the first time, the immune system produces IgE in abnormally large amounts. IgE sensitizes mast cells and basophils by binding to mast cells and basophils. IgE binds to mast cells and basophils through its specific receptors. If this same individual contacts the cognate allergen for the second time, the body produces even more IgE antibodies; the IgE bind to their receptors on mast cells and basophils and trigger the massive release of varieties of preformed inflammatory mediators. Among the most important mediators released by mast cells and basophils are
- prostaglandin (PG) D2
- platelet activating factor
Moreover, tissue mast cells, scattered over connective tissues of the body are alert constantly to direct physical tissue damage. They respond to physical tissue damage (such as cut on the skin) by releasing preformed inflammatory mediators form their cytoplasmic granules.
Mast cells attract eosinophils
Mast cells secrete chemical agents and cytokines that act as chemoattractant molecules, attracting eosinophils to the site of reaction. The principal chemotactic agents include histamine and interleukin (IL)-5. Moreover, IL-5, also called eotaxin because it induces the chemotaxis of eosinophils stimulates the proliferation of eosinophils.