Inflammation

Inflammation

it is a protective response of the body tried to eliminate the initial cause of cell injury as well as necrotic cell and tissue that result from the original insult and it is either acute or chronic
Acute inflammation
It is an immediate and early response of short duration characterized by exudation of protein rich fluid and accumulation of acute inflammatory cells.
Mechanism of acute inflammation
1-vascular changes:
2-cellular events
1-VASCULAR CHANGES
A-change in blood vessels caliber and blood flow WHICH INCLUDE
1-it starts with transient vasoconstriction, last for few minutes flow by arteriolar vasodilatation so more blood will flow lead to capillary engorgement .
2-The microcirculation become permeable so protein rich fluid will escape to interstitial spaces so red blood cell become more concentrated result in increase blood viscosity , this lead to stasis .
3-As stasis develop neutrophil accumulate at the margin of blood vessels and this is called margination.
B-increase in vascular permeability:
vasodilatation increase in blood flow lead to increase in hydrostatic B.P causing escape of fluid outside the blood vessels, this fluid is micro filtrate of plasma but with little protein and called transudate , this last few minutes then stop, once the vascular permeability increase exudation of protein rich fluid will occur which accumulate in interstitial tissue forming inflammation exudates (oedema).

Mechanism of increase vascular permeability

1-endothelial cells contraction forming gap through which the fluid can escape., occur in venule , caused by vascular mediator, more common, rapid and of short duration
2-Direct injury to the endothelial cell : occur in the arteriole, capillary and venule, caused by sever injury as in toxin, burn and chemical rapid but of long duration.
3-Leukocyte depending injury: occur in venule of systemic circulation and in the pulmonary capillaries occur late & of long duration.
4-increase transcytosis : it occur at the venule & fluid escape through canals formed by fusion of uncoated vesicle , mediated by a mediator called VEDGF(vascular endothelial derived growth factor).
5-exudation occur at the site of angiogenesis and here the endothelial cell continue to leak until it differentiate and form endothelial junction, in addition these endothelial cell show increase in expression for vascular mediator VEDGF( vascular endothelial growth factor).






2-cellular events:
the escape of leukocyte from blood vessels to the interstitial tissue pass at different steps:
1-margination and rolling: the leukocyte are pushed out from the central axial blood flow & accumulate at the margin of b.v this called margination, then these leukocytes tumble on the endothelial cell and stick along the blood vessels this process is called rolling , transient adhesion seen in rolling happen by selectin family which are receptor present on both endothelial & leukocytes . .
2-Adhesion and transmigration: leukocytes become firmly stick to the endothelial cell & crawl between them and this called diapedesis ,occur at the levels of venules in the systemic circulation and in the capillary of pulmonary circulation by the aid of specific immunoglobulin family present on endothelial cells that react with integrin present on leukocytes ..
3-chemotaxis : accumulation of leukocytes at the site of injury along a chemical mediator which is exogenous or endogenous substances called chemotactic substances such as bacterial product , component of a complement system (C5a) , cytokines and product of arachidonic acid metabolism.
the predominant cell is neutrophil which appear few minutes after the onset of inflammation and reach the peak within 24hours while monocyte usually appear later. However in certain type of acute inflammation as in viral inflammation, lymphocyte is predominate .



4-Phagocytosis and degranulations: which are the two main benefit of leukocyte exudation. (function of Neutrophil )
Phagocytosis has three steps:
*Recognition &Attachment
*Engulfment
*Killing
A / recognition and attachment of particles to be removed to certain receptor present on the leukocyte and this is enhanced by certain plasma protein called opsonin which are of three types:
*F c fragment of IgG class.
*Activate third complement system C3b.
*collectin .
B/ engulfment: once the foreign particle attach to the receptor of leukocyte then later pass a pseudopodia around it which fuse to form phagocytic vacuoles called phagosome which combine with lysosome to form phagolysosome this process called engulfment
C/ killing and degranulation of bacteria: occur by two mechanism :
1-oxygen independent mechanism: happened by the help of lysosome enzyme and it is less important than the second mechanism.
2-Oxygen dependant mechanism: phagocytosis stimulate consumption of oxygen by the action of NADPH oxides so the oxygen converted into super oxide ,some of which is further change to hydrogen peroxide and both (super oxide and hydrogen peroxide) act as a bactericidal by the help of myeloperoxidase (MPO) forming hypochlorous acid which is more potent bactericidal than H2O2.




Cardinal signs of acute inflammation :

Hottness due to hyperemia .
Redness - - - .
3- swelling due to oedema.
Pain due to increase tissue tension by oedema & to release chemical mediators
Loss of function due to swelling & pain .
.
Types of acute inflammation (macroscopic features):
It depends on the texture and nature of inflamed tissue & the magnitude of inflammatory exudates so we have Many types:
1-Occur on the skin we can see the cardinal signs of acute inflammation thats to say redness, swelling ,hotness , pain and loss of function.
2-Serous inflammation: this happen when the inflammation occur in a serous cavity such as peritoneum, pericardial and pleural, characterized by excess accumulation of fluid with little fibril and the tissue appear dull and opaque.
3-Fibrinous inflammation: it also occur in the serous cavity follow serous inflammation and characterized by excess deposition of fibrous tissue as in fibrinous pericarditis seen in rheumatic heart disease.

4-Catarrhal inflammation: seen in the mucous membrane and characterized by excess secretion of watery mucoid fluid as in common cold which is viral infection.
5-Mucopurulent inflammation: follow catarrhal inflammation in which the desquamated epithelium or the bare area is invaded by secondary bacteria which stimulate heavy neutrophilic infiltration, so the discharge become purulent.
6-Pseudo-membranous inflammation: seen in diphtheria and pseudo-membranous colitis .characterized by extensive necrosis of the surface epithelium associated with marked inflammation in the underlying tissue in which fibrinogen is coagulated into fibrin together with bacteria, dead & living neutrophil, RBC form pseudo-membranous.
7-Suppurative inflammation: which characterized by the formation of large amount of pus occur in pyogenic infection thats to say infection by pus forming bacteria such as streptococcus and staph.
Microscopic feature of acute inflammation
Accumulation of oedema, which is pale pink together with fibrin and neutrophil, the blood vessels is dilated, congested and showing margination of neutrophil.
Result of acute inflammation:
1-resolution: this happen if the causative agent is removed with minimal tissue injury, and here the inflamed tissue return completely to its previous normal appearance .
2-healing by fibrosis:
A -heavy deposition of fibrin occur during early stage of acute inflammation which can not be removed totally by fibrinlytotic system, so it undergo organization lead to the granulation tissue formation which later mature into fibrous tissue.
B-It may occur if inflammation associated with death of large amount of tissue in which healing occur by granulation tissue formation.
c- If acute inflammation changes into chronic one.


3-suppuration: is formation of pus which occur in pyogenic infection here the m.o. secret a strong toxin which cause extensive necrosis this lead to heavy infiltration of neutrophil which die and release their lysosomal enzyme, this enzyme liquefy the necrotic tissue and convert it into creamy sticky material called pus, the pus is composed of bacteria, dead and living neutrophil & tissue debris, suspend into inflammatory exudates
Usually the pus is formed in the cavity forming abscess these abscess are drained either by doctor or by itself and if it is not drain it changes into chronic abscess .
4-If the causative agent persist, it will lead to chronic inflammation.

Localize effects of inflammation :

* beneficial effects of inflammatory exudate:
dilution & removal of toxin by lymphatic.
The presence of antibody which enhance phagocytosis of bacteria & virus by phagocytic cells
Fibrin formation from fibrinogen in the exudates which delay bacterial spread & enhance its phagocytosis ,
Exudates contain antibiotic which help in bacterial killing .
Promotion of immunity : bacteria & toxin carried to the regional L.N enhance immune response in the form of antibody or cellular response ,
Harmful effects :
swelling can cause serious mechanical effect e.g. acute laryngitis may cause difficulty in breathing due to narrowing in the lumen .
acute inflammation may affect the function of the organ either directly or by interference with its blood supply as in acute encephalitis which increase the intracranial pressure causing coma.

Can cause hypersensitivity reaction as in asthma .

Systemic effect of acute inflammation
1-Leukocytosis: increase in the number of circulating leukocyte in the peripheral blood this happen due to release of substance called CSF (colony stimulating factor ) which enhance the proliferation of myeloid precursor
Netrophilic leukocytosis is a feature of acute bacterial infection while eosinophilic leukocytosis is seen in the parasitic infection and allergic condition while lymphocytosis is seen in acute viral infection.
2-fever which caused by endotoxin released from bacteria which stimulate macrophage to secrete endogenous pyrogen, this substance has the same action of interleukin 1. It effect the anterior hypothalamus either directly or by release prostaglandin E, this carry the information to the vasomotor center in posterior hypothalamus which cause sympathetic nerve stimulation causing contraction in circulation in the skin so decrease the heat loss at the same time it enhance heat production by increase muscular tone and increase in the metabolism of the liver and skeletal muscle.
3-Weight loss: seen in prolong infection due to release of interleukin 1 and TNFa.(tumour necrotizing factor A)
4-abnormal protein synthesis: include reduction in albumin synthesis with increase in the production of C-reactive protein, complement component fibrinogen and amyloid A protein, the exact mechanism is unknown may be due to release of interleukin 1,6 or due to tumor necrotic factor a (TNFa).
5-secondary amyloidosis.


chemical mediator: certain substances released during inflammation and it is responsible for vascular changes and cellular infiltrate, it has certain characters include:

1- mediator is either found in the plasma which is formed in the liver as kinin , coagulative ,fibrinolytic & complement system . they circulate as inactive form & it should be activated to do its biologic effects .OR may produce locally at the site of inflammation and either sequestrated within the granules inside the cells as histamine or it forms denovo at the time of inflammation as prostaglandins
2- the majority of mediator produce its effect by binding to certain receptor present on the target cells or it acts directly by enzymatic or toxic effect .
3- Mediator act either on few target cells or has wide spread site of action.
4- Its function is highly regulated & once its activated it either decay as in arachidonic acid derivative or inactivate by enzyme as in kinin or removed as free radical which is removed by antioxidants .
mediator may stimulate the target cells to secrete secondary mediators which either potentate the action of primary mediator or opposite it .

A-Cell derived mediator: include

1-Histamine: found in the granules of mast cells mainly ,platelets and eosinophil and it is released by deregulations of mast cell which occur due to various stimuli. Its action causes vasodilatation and increase vascular permeability. Rapidly removed by histaminase .
2-Serotonin: secreted from platelet it has the same action of histamine.
3-Platelet activating factor: which cause platelet aggregation and degranulation result in increase vascular permeability, leukocyte adhesion and stimulation the formation of arachidonic acid
4-lysosomal enzyme: which is secreted from neutrophil after its death & from macrophage when engulf large particles . e.g neutral protease that cause destruction & forming tissue injury also stimulate cleavage of C3 & C5 , its effect is controlled by anti protease which if deficit result in excess tissue destruction at the site of leukocyte infiltration e.g emphysema .
5-arachidonic acid derivative: called (eicosanoid) which include prostaglandins, leukotriens, and lipoxines. arachidonic acid is usually stored in the membrane phospholipids and by the action of phspholipase it is release which further metabolized by 2 pathway, either by cyclo-oxygenase which form prostaglandin and thromboxin A2 or by lipoxygenase forming lipoxine and leukotrienes


The type of prostaglandins (PG) form depend on the type of cell activated PGI,2 & Thromboxin A2 formed in the platelets & endothelial cells .
Thromboxine A2 causing vasoconstriction & promote platelet aggregation While prostacyclins secrete from neutrophil & macrophage causing vasodilatation & potentiate oedema ,inhibit platelet aggregation , & can cause fever & pain if inject in the skin.
Leukotrienes cause vasoconstriction , increase in vascular permeability & smooth muscle contraction & all called SRS ( slow reactant substance of anaphylotoxin .
Lipoxins cause vasodilatation, inhibit neutrophil chemotaxsis & stimulate monocyte adhesion.
Steroid act as anti-inflammatory by blocking phospholipase enzyme while aspirin & nonsteroidai anti-inflammatory block cyclo-oxygenase enzyme & inhibit fever & pain .
B/ plasma derived mediator:
1-kinin system: which convert kininogen into bradykinin which increase vascular permeability, stimulate muscle contraction and cause pain if injected into skin however bradykinin is rapidly metabolized by kininase enzyme so it has short duration of action.
2-Coagulation and fibrinolytic system: activation of coagulation system convert soluble fibrinogen into insoluble fibrin, while activation of fibrinolytic system break fibrin into fibrin degenerated produced, all these substances has chemotactic effect and cause increase vascular permeability.
Complement system: it is a plasma protein play a role in inflammation and immune response by the formation of MAC (membrane attack complex), this complex make a hole in the wall of bacteria and lyses it. Complement system is composed of (9 )subgroups (c1-c9),





They exist its function after activation mainly of C3 component which either activated by classical way by antigen antibody complex or by alternative way by bacterial polysaccharide .
Mode of action :
vascular effect mediated via C3a & C5a which also called anaphylotoxin , causing increase vascular permeability .
- Leukocyte activation & adhesion .
Phagocytosis mediated by C3b which act as opsonin .

Chronic inflammation:

it is a type of inflammation of prolong duration which last weeks or months, in which active inflammation cause cell injury and healing can occur at the same time, chronic inflammation characterized by:
1-infiltration by mono nuclear cell such as lymphocyte, monocyte and plasma cell.
2-Tissue destruction mediated by inflammatory cell.
3-evidence of healing which include new blood vessel formation called angiogenesis and fibrosis.
Cause of chronic inflammation:
1-it may follow acute inflammation and this happen if the causative agent persist in the area or due to interference with the process of healing.
2-It may arise denovo i.e. arise from the beginning as chronic inflammation as in:
A-viral infection.
B-Persistence microbial infection as in T.B .
C-Could be due to prolong exposure to toxic agent which could be exogenous as in silicosis or endogenous as in chronic hypercholesterolemia which lead to atherosclerosis.
D-Auto immune, here the body form antibody against itself antigen as in rheumatoid arthritis.


Grossly ; macroscopic appearance is variable , either present as chronic ulcer , ch abscess , ch sinus which tract the underlying structure with skin or as diffuse thickening in the wall of an organ .

Microscopic feature also variable however they share the following characters :

1- the reaction is productive i.e/ formation of new fibrous tissue which is

at the beginning is cellular & vascular with little collagen later the cellularity & vascularity decrease but with increase collagen .
2- cellular infiltrate is pleomorphic i.e different types of cells could be seen , however in classical ch inflammation lymphocyte , plasma cell & macrophage are seen . Sometime macrophage are activated & change into epitheloid cells & in certain infection macrophage join to form giant cell .

Mediator of ch inflammation :

Macrophage is the main cell in ch inflammation which is form from circulating monocyte after leaving b.v it change into tissue histiocyte , Then it undergo activation either by gamma interferon that secreted from T lymphocyte or by non immune mechanism as endotoxine or by other chemical mediator . Active macrophage secret substances that cause :
tissue injury by release of certain substsnces as reactive oxygen species , arachidonic acid metabolite & protease .
it cause fibrosis by release of growth factor , TNFa . IL-1 & angiogenesis factor .
In addition macrophage activate lymphocyte by the presence of antigen presenting molecules on the surface of macrophage ,so lymphocyte & macrophage stimulate each other until the triggering antigen is removed .



Granulamatous inflammation:
Certain type of chronic inflammation characterized by formation of epitheliod granuluma
Causes of granulomatous inflammation:
1-Bacterial as in T.B., leprosy, gumma of syphilis and cat cat scrach disease.
2-Fungal infection as in histoplasma capsulatum.
3-Parasitic as in schistosomiasis.
4-Inorganic as in silicosis.
5-Foreign body as in talc.
6-Unknown case as is sarcoidosis.


Inflammatory cells :
Polymorphnuclear Neutrophilis:
It constitute 40-75% of circulating leucocytes , characterized by the presence of granules in their cytoplasm that contain many substances as myeloperoxidase , alkaline phosphates , proteases . it increase in blood & tissue in acute bacterial infection .Its function in inflammation include :
1- Initial phagocytosis of m.o as they form the 1st line of body defense in bacterial infection .
2- Engulfment of A.g A.b complex & non microbial materials .
3- Harmful effect of neurtophil is destruction of the basement membrane of glomeruli & small b.v

Eosinophils :

Larger than neutrophil but fewer in number form 1-6% , it share some structural & functional similarity to neutrophils , it increase in the following conditions :
- allergic condition .
- Parasitic infection .
- skin disease .
- certain malignant lymphoma.

Basophils :

It form 1% of circulating leucocytes , it contain granules rich with histamine & heparin & have receptor for IgE , its role of inflammation :
1- Immediate & delay type of hyper sensitivity .
2- Release of histamine by IgE sensitized basophil.

Lymphocyte :

It constitute 20-45% of circulating leucocytes. Present in the blood , L.N , spleen , thymus & mucosa of GIT .
It play a role in antibody formation ( B lymphocyte) & in cell mediated immunity ( T lymphocyte). It increase in :
- IN tissue : it is the dominant cells in chronic inflammation & in acute viral infection .
In blood it increase in certain chronic infection as T.B.


Mononuclear phagocyte system:
macrophage : Is the main cell in ch. Inflammation , it derived from circulating monocyte .it found in different tissue under different name forming what is called Mononuclear phagocyte system as ; * Macrophage in inflammation ,* histiocyte in C.T,* Kuffer cell in liver ,* Alveolar macrophage in lung ,* Microglial cell in nervous system ,* Free & fixed macrophage in sinusoid of L.N , spleen & B.M.
These cells play a role in immune system as well as in inflammation .
Role of macrophage in inflammation :
1- phagocytosis .
2- Macrophage on stimulation by interferon which released from T lymphocyte change into large , flat , pink cell called epitheloid cell which has secretory functions( secrete many active substances like ( AA metabolite , protease , growth factor , plasminogen activator , some coagulation factor as factor v , ----)

Giant cell

When the macrophage fail to deal with particle to be removed they fuse together forming multinucleated giant cell.which is of many types :
1- foreign body giant cell
2-Langhans giant cell.
3-Touton giant cell : multinucleated cell with vacuolated cytoplasm due to high lipid content as in xanthoma .
4-Tumour giant cell :large cells vary in shape with multiple hyper chromatic nuclei form from dividing malignant cell as in carcinoma of liver .


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