Pathophysiology_FULL

ticket “wandering only from the blood to the interstitium, lymphocytes possess by so called

“ticket return” and can traverse the vessel there and back. Being the first in emigration, neutrophils predominate in the tissue and infiltrate it during first 6-24 hours but then, on 2-4- day they partially are replaced by the monocytes. Later the lasts are transformed into inflammatory tissue macrophages. In this conversion they change not only the size, becoming lager, but the shape of the nucleus. The macrophages have a long-standing course in the tissue and dominate as the cellular unit in the site of chronic inflammation.

9. Mediators of inflammation. The sources and mechanisms of their action in course of an acute inflammation.

10. Acute phase response. Definition and the main mechanisms of its realizing. The most important mediators which are involved in this defensive reaction.

Definition: APR is a non-specific reaction of whole organism to severe injury with activation of four life-important systems: nervous, endocrine, hematopoietic, and immune system. To this characteristic must be added destructive catabolic processes in form of proteolysis and lipolysis. Special role in APR belongs to changed metabolism in the liver, when the last actively synthesizes so called acute phase response proteins detriment to other proteins, for example the albumens and transferrin.

Mediators of an acute phase response

IL-I

Local effects:

Macrophages: stimulation of chemotaxis and phagocytosis, superoxide, TNF and IL-6 production and expression of MHC class II on the macrophages surface

Neutrophils: activates chemotaxis, phagocytosis, superoxides production, enhances adhesive properties of endothelium and forces leukocyte emigration; stimulates of neutrophil degranulation

T-lymphocytes: increase synthesis of IL-2 and the receptors to IL-2 to their mitogen activity

B-lymphocytes; amplifies (makes effort) IL-2 synthesis and expression of its receptors on the cell surface , so as IL-4 and MHC-class II. Increases proliferation of pre-activated B- cells

NK+ cells: makes effort cell cytotoxicity, increases IF-gamma and IL-2 production by the cells

Fibroblasts: activates prolferation, induction of IL-6, interferon gamma, CSF (colony stimulating factors), and PgE-2 secretion

Mast cells and basophils: increases histamine release

Endothelium: stimulation of proliferation, increases adhesion and thrombogenic potential, and secretion of NO

Distant effects:

Bone marrow: stimulation of polypotent cells proliferation and acts as early cytoclone

Bone and cartilage: stimulation of collagenase activity, osteoclasts and PGE-2 production, destruction of the bones and cartilage lysis. Enhances proliferation of sinovial fibroblasts and chondrocytes

Strip muscles:proteolysis, loss of water and increases prostaglandins synthesis

Liver: increases synthesis of acute phase response proteins via IL-6 synthesis

CNS: via increased PgE-2 content in the brain provokes fever and inhibits the centers of appetite that leads to serious loss of weight. Destructive processes in the bones and wasting strip muscles may to be inserted in the list of weight loss causes

TNF

TNF possesses by many properties of the IL-1 but, on the other hand, local effects of IL are stronger than the same of TNf, but must be add ed that TNF enhances the effect of IL-1. However, they both have much in common:

Stimulate adhesion molecules expression on the leukocytes, endothelial cells and chemotaxis of the leukocytes

Provoke elaboration of the oxidants in the leukocytes

Make lymphocytes to produce such growth factor for lymphocytes as IL-2

Enhance production of lymphotoxin by the lymphocytes, stimulate production of IFgamma by the macrophages, and antibodies by B-lymphocytes

Stimulate many cells of the site of inflammation (macrophages, endothelium and fibroblasts) to produce G- and GMCSF ( granulocytic an granulocyticmonocytic colonystimulating factors).

They both are responsible for such symptom as fever

stimulate production of the acute phase response proteins by the liver via IL-6

The difference between TNF and IL-1

TNF is synthesized by the lesser number of the cells, and first of all, by the macrophages and leukocytes. Moreover, it has more cytotoxic effect, increases HLA II and I classes of molecules on the corresponding cells and, such way, provides better immune recognition of the foreign material, mostly, the neoplastic cells. Can’t activate T-cells directly but possesses by antiviral effect “in vitro”.

One of the possible mechanisms of cachexia is inhibition by TNF-alpha the lipoproteinlipase activity, arranging in normal the lipid stores in a fat tissue. Another one explanation is associated with an inhibition of the centers of appetite in the hypothalamus. The third mechanism is connected to myolysis and loss of water by the muscles.

IL-6

The main sources of the mediator are the following cells: activated endothelium, macrophages, fibroblasts, and lymphocytes