Pathophysiology of inflammation
- Definition :
- Inflammation or inflammatory reaction is the response of living, vascularized tissues to an attack.
- A component of innate immunity, it is generally protective
– participating in natural defense processes
– and repair of damaged tissues
Recognized by CELSUS, in the 1st century ,
– by four clinical signs
– the cardinal signs of the inflammatory reaction: Rubor et tumor cum calore et dolor
Redness and swelling, with warmth and pain
2. Causes of inflammatory reactions
The causes are multiple and represent the pathogens. They are:
🡪 either exogenous:
. Infection (bacteria, viruses, parasites, fungi)
. Physical agents: trauma, radiation, heat, etc.
. Chemical agents: caustics, toxins…
. Foreign bodies
🡪 either endogenous:
. Vascularization defect: inflammatory reaction secondary to necrosis of ischemic origin.
. Dysimmune aggression (abnormality of the immune response, allergies, autoimmunity, etc.)
These causes determine cellular and tissue lesions which will trigger inflammation.
Please note that:
– Inflammation is not synonymous with infection but an infection is a cause of inflammation,
– The same pathogen can cause different inflammatory reactions depending on the host: hence the importance of host-related factors (e.g. the state of immune defenses).
3. Means of defense of the organism.
They are of 2 types:
– Static: Skin and mucous membranes
– Mobile: Mobile cells: polymorphonuclear cells (PN), macrophages, lymphocytes.
Humoral substances produced by cells participating in inflammation can have an action:
– Non-specific: vasodilator agents
– Specific: neutralization
4. Main stages of the inflammatory response:
An inflammatory reaction to an aggressive agent involves the successive implementation of non-specific and specific defense mechanisms:
4.1. Non-specific means of defense:
Their characteristics are:
– Rapid play (acute clinic)
– Non-selective triggering (any aggressor agent)
– Absence of prior immunological recognition of the aggressor
– Rapid cellular response (to polymorphonuclear cells)
– Rapid vascular response (vasomotor phenomena )
4.2. Specific means of defense
Their characteristics are:
– Later and longer duration of involvement (chronic clinical)
– Prior sensitization and initiation of an immune response
– Slow cellular response: macrophages, lymphocytes, plasma cells, fibroblasts
– Slow vascular response: neoangiogenesis.
Pathophysiology of inflammation
5. Modalities of expression of the inflammatory reaction:
Under physiological conditions, the body’s defenses are constantly called upon to ensure the maintenance of the integrity of the internal environment: this homeostasis reaction has no clinical translation, it only has a microscopic morphological translation.
Sometimes inflammation can be pathological: it is called disease inflammation.
This pathological character has as its origin either:
– the particular aggressiveness of the pathogen,
– its resistance to the use of the body’s defense mechanisms,
– exaggeration of normal phenomena,
– functional deficits.
This process includes:
– local phenomena: inflammation occurs in vascularized connective tissue (tissues without vessels (cartilage, cornea) are unable to develop a complete inflammatory reaction).
– general phenomena, expressed biologically by the inflammatory syndrome and clinically in a variable way, most often by fever and possibly a deterioration in the general condition .
Inflammation involves cells, vessels, extracellular matrix changes, and many chemical mediators that can be pro- or anti-inflammatory.
Although the course of inflammatory reactions presents general morphological characteristics and common mechanisms, they will differ from each other depending on
- of the nature of the pathogen,
- of the affected organ,
- of the physiological terrain of the host.
These elements determine the intensity, duration of the inflammatory reaction and the appearance of the lesion.
6. Relationship between pathophysiology and clinic:
An inflammatory disease reaction, with an acute clinical manifestation, corresponds to an immediate response to an aggressive agent, of short duration (a few days or weeks). Acute inflammations heal spontaneously or with therapy, but can leave after-effects if tissue destruction is significant.
These inflammations correspond to the activation of non-specific defense means sometimes associated with the activation of specific defense means for a short duration.
An inflammatory disease reaction, with a chronic clinical manifestation, corresponds to an inflammation that has no tendency to spontaneous healing and which evolves by persisting or worsening over several months or several years.
We can distinguish two types of circumstances in which chronic inflammation occurs:
1) acute inflammations developing into prolonged subacute and chronic inflammations when the initial pathogen persists in the tissues (incomplete debridement) or when acute inflammation recurs repeatedly in the same organ, causing tissue destruction with each episode that is less and less well repaired.
2) Inflammations can sometimes manifest themselves immediately in an apparently chronic form.
The involvement of non-specific defense mechanisms has gone unnoticed because it is brief or asymptomatic. This is often the case for conditions where dysimmune mechanisms are predominant (example: chronic hepatitis secondary to infection by hepatitis B or C virus).
7. Involvement of non-specific defense mechanisms and acute inflammation.
An inflammatory disease reaction, with an acute clinical manifestation, corresponds to an immediate response to an aggressive agent, of short duration (a few days or weeks). The aggression, cellular destruction, debridement and repair follow one another in rapid succession.
7.1. Cells involved
7.1.1. Polymorphonuclear leukocytes (PN)
During the first 6 to 24 hours, polymorphonuclear cells migrate from the microcirculation to the inflammatory site by diapedesis (active crossing of the vascular walls).
7.1.1.1. Polymorphonuclear neutrophils (PNN) play a major role.
Their different functions are:
– Phagocytosis : capacity to encompass, in the cytoplasm of the phagocyte, a living or inert foreign particle, usually followed by digestion of this particle by lysosomal enzymes.
– Regurgitation: capacity to release phagocytosis products (phagocytosed element and enzymes) into the extracellular matrix.
– Bactericidal action: production of free radicals
Bactericidal but causing damage to surrounding tissue, and production of bactericidal enzymes (lactoferrin, lysozyme).
Becoming PNNs:
– production in the bone marrow stimulated by pro-inflammatory cytokines,
– migration under the influence of chemotactic factors in 20 minutes,
– lifespan: 20 days, eliminated by apoptosis or exocytosis.
7.1.1.2. Eosinophilic NPs complement the action of neutrophils:
Their different functions are:
– Limited phagocytosis (immune complexes)
– The release of enzymatic proteins (arylsulfatases, histaminases) playing a role as “buffer” proteins against the degranulation of basophilic NPs.
In excess, these enzymes can form crystals (Charcot Leyden crystals) observed in asthma, a pathology causing repeated degranulations of numerous eosinophilic polymorphonuclear cells.
Pathophysiology of inflammation
7.1.1.3. Basophilic NPs and mast cells:
Basophils are present in circulating blood. Mast cells are non-circulating cells present in tissues. Their enzyme content is comparable.
They play an important role in vasomotor phenomena associated with inflammatory reactions through the release of the enzymatic content of their cytoplasmic granules: histamine and heparin.
7.1.2. Platelets
Platelets will play a fundamental role in:
– hemostasis through their aggregation,
– proteolysis of the extracellular matrix at the inflammatory site by degranulation of their lysosomal enzymes (hydrolases, cathepsins),
– the release of arachidonic acid derivatives (prostaglandins, leukotrienes and thromboxanes) having local actions (vasomotion, attraction of polymorphonuclear cells) and general effects (fever).
7.2. Circulating plasma mediators.
Their main characteristics are:
– Their presence in plasma in the form of precursors,
– Multiple systems with complementary or antagonistic actions,
– Role in both the initiation and maintenance of inflammation .
7.2.1. The kininogen-kallikrein-kinin system:
Polypeptides with vasoactive action formed from plasma kininogen through the action of enzymes: kallikreins.
The most important member of this polypeptide family is bradykinin (vasodilator) . Kinins are potent vasodilators activated within the first hour of the inflammatory reaction. They increase vascular permeability and are the main cause of edema during inflammatory reactions.
Their action is powerful but brief because their lifespan is short.
7.2.2. The complement system: a cascade system:
The complement system comprises a set of serum proteins (complement factors) whose activation is carried out by cascade proteolysis reactions.
It plays an important role in:
– chemotaxis of PNN,
– opsonization of bacteria. Certain complement factors (C3b, etc.) adhere to bacteria, facilitating their phagocytosis by PNNs and macrophages,
– vasodilation (C3a: anaphylatoxin) by causing the degranulation of mast cells, polymorphonuclear basophils and the release of vasodilatory enzymes (histamine, etc.).
7.2.3. Coagulation-fibrinolysis systems
This is a system in equilibrium in the normal state.
Coagulation is activated by the aggressors: a cascade of proteolysis results in the production of fibrin from fibrinogen.
Fibrin limits the inflammatory focus. Fibrinolysis is activated by cell necrosis: plasmin degrades fibrin by producing fibrin degradation products (PDF).
7.2.4. Plasma protease inhibitors:
They intervene in the regulation of the previous systems, the complete activation of which would be lethal. Ex: alpha1-antitrypsin.
7.3. Mediators of cellular origin
The direct action of the cells is completed by the release of:
7.3.1. Arachidonic acid derivatives
Released under the influence of phospholipase A2 (mainly from neutrophils and platelets):
– Prostaglandins: powerful vasodilators promoting increased vascular permeability,
– Leukotrienes: playing a role in the chemotaxis of PNN, promoting platelet aggregation and having a vasoconstrictor effect,
– Prostacyclin: antiplatelet and vasodilator,
– Thromboxane A2: powerful platelet aggregator and vasoconstrictor.
7.3.2. Vasoactive amines
Basophils and mast cells release histamine ; platelets release serotonin , both potent vasodilators.
7.3.3. Cytokines and growth factors:
Cytokines are peptides or proteins produced by many cells.
They act through membrane receptors, on the cell that produces them (autocrine effect), on nearby cells (paracrine effect) and on cells located at a distance (endocrine effect).
They are produced by lymphocytes, monocytes-macrophages and fibroblasts.
These are cellular cooperation factors which are at the origin of three main effects:
- Mediation of natural immunity (interferons causing non-specific antiviral activity),
- Stimulation of hematopoiesis ( colony stimulating factors ) and
- Modulation of the activity of many cells involved in inflammation.
7.4. Morphological expression of the implementation of non-specific defense means
7.4.1. The homeostatic response
This is the physiological inflammatory reaction without clinical translation.
It includes three main phases :
7.4.1.1. Limitation phase
It is mediated by an immediate vascular response including:
– active congestion: vasodilation by opening of the precapillary sphincters caused by the chemical mediators already seen,
– inflammatory edema: by increase in capillary pressure after opening of the precapillary sphincters and secondarily by modification of vascular permeability,
– This is associated with microthrombosis at the periphery of the lesion focus and interstitial hemorrhage.
Pathophysiology of inflammation
7.4.1.2. Detersion phase
This involves the elimination of foreign or necrotic elements present at the inflammatory site. It is carried out by neutrophils that have migrated to the inflammatory site by diapedesis and by macrophages. To carry out the detersion, these cells use their phagocytosis capacity.
7.4.1.3. Repair phase
After debridement, the inflammatory site is the site of a decrease in vascular and cellular responses. This is followed by activation of the fibroblast system with cell multiplication and collagen synthesis . Tissue repair can take two forms: regeneration and healing . When tissue destruction is partial, it can return ad integrum and regain its functions: this is regeneration.
Healing results in newly formed connective tissue which replaces the destroyed tissue: healing is mutilating.
7.4.2. Acute inflammation “disease”
Its pathophysiology is based on the exaggeration of normal vascular and/or cellular responses or, more rarely, is linked to problems of congenital functional deficits.
7.4.2.1. Exaggeration of the vascular response
🡪 Exudative edematous inflammation. An exaggeration of vascular permeability results in an exudation phenomenon causing interstitial tissue edema. An exudative edematous inflammation located in a cavity (pleura, peritoneum) causes an effusion.
An exudative edematous inflammation located in a canal (the ear canal, etc.) is the cause of a discharge.
When the exudate is poor in fibrinogen: it is said to be serous, when it is rich in fibrinogen, it coagulates into a fibrin network and is said to be sero-fibrinous . In this case, during debridement either the lysis of the fibrin by the enzymes of the polymorphonuclear cells is complete, or the debridement is incomplete and a fibrous tissue will form in place of the fibrin: this is the fibrous organization.
🡪 Hemorrhagic inflammation. The increase in vascular permeability, particularly through activation of fibrinolysis during, for example, septicemia or disseminated intravascular coagulation (uncontrolled coagulation in the body’s capillaries) is the cause of hemorrhagic inflammation.
🡪 Thrombotic inflammation. Any endothelial lesion during an inflammatory reaction is the cause of the activation of the coagulation pathway. Thrombosis during physiological inflammation aims to slow the dissemination of the aggressor agent. Thrombotic inflammation occurs in a tissue that is initially normally well irrigated where excessive activation of coagulation is the cause of extensive thrombosis. Their side effect is anoxia causing ischemic necrosis.
7.4.2.2. Exaggeration of the cellular response
🡪 Suppurative inflammation: Inflammation characterized by the massive presence of pyocytes (altered polymorphonuclear neutrophils).
Pus is a mixture of pyocytes, fibrin and tissue necrosis material. Most frequently, it is “pyogenic” bacteria that are at the origin of suppurative inflammations. The presence of pus must therefore lead to a bacteriological examination.
Suppurative inflammation can occur in several forms:
– An abscess is a limited suppuration collected in a solid organ (subperiosteal abscess),
– Empyema is a limited suppuration collected in a hollow organ (sinus empyema),
– Phlegmon is a suppuration that does not collect, spreads and takes on a regional character (tonsillar phlegmon).
Pathophysiology of inflammation
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