acute inflmmation

Acute inflammation

Definition
Inflammation is the response to injury of a tissue and its microcirculation and is characterized by elaboration of inflammatory mediators as well as movement of fluid and leukocytes from the blood into extravascular tissues.


“Inflame” – to set fire.Inflammation is “A dynamic response of vascularised tissue to injury.”It is a protective response.It serves to bring defense & healing mechanisms to the site of injury.

Acute inflammation

Chronic inflammation
Repair
Resolution
Abscess
Injury
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Cardinal Signs of Inflammation

Redness : Hyperaemia. Warm : Hyperaemia. Pain : Nerve, Chemical mediators. Swelling : Exudation Loss of Function: Pain



Inflammation is best viewed as an ongoing process that can be divided into phases. Initiation results in a stereotypic, immediate response termed acute inflammation. The acute response is characterized by the rapid flooding of the injured tissue with fluid, coagulation factors, cytokines, chemokines, platelets and inflammatory cells, and neutrophils in particular. Amplification depends upon the extent of injury and activation of mediators such as kinins and complement components. Additional leukocytes and macrophages are recruited to the area.


Destruction of the inciting agent by phagocytosis and enzymatic or nonenzymatic processes reduces or eliminates foreign material or infectious organisms. At the same time, damaged tissue components are also removed, paving the way for repair to begin. Termination of the inflammatory response is mediated by intrinsic anti-inflammatory mechanisms that limit tissue damage and allow for either restoration of tissue, with return to normal physiological function, or repair and the development of scar in place of normal tissue.

Tissue oedema

Neutrophil margination …. And emigration

Acute Inflammation: Vascular Events

Among the earliest responses to tissue injury are alterations in the anatomy and function of the microvasculature, which may promote edema. These responses include:


Transient vasoconstriction of arterioles at the site of injury is the earliest vascular response to mild skin injury. This process is mediated by both neurogenic and chemical mediator systems and usually resolves within seconds to minutes. Vasodilation of precapillary arterioles then increases blood flow to the tissue, a condition known as hyperemia. Vasodilation is caused by release of specific mediators and is responsible for redness and warmth at sites of tissue injury.


3. An increase in endothelial cell barrier permeability results in edema. Loss of fluid from intravascular compartments as blood passes through capillary venules leads to local stasis and plugging of dilated small vessels with erythrocytes. These changes are reversible following mild injury: within several minutes to hours, the extravascular fluid is cleared through lymphatics.


Edema is accumulation of fluid within the extravascular compartment and interstitial tissues Transudate is edema fluid with low protein content (specific gravity <1.015). Transudates tend to occur in noninflammatory conditions, where the endothelial barrier remains intact and prevents the loss of large molecules from the vasculature. Exudate is edema fluid with a high protein concentration (specific gravity >1.015), which frequently contains inflammatory cells. Exudates are observed early in acute inflammatory reactions and are produced by mild injuries, such as sunburn or traumatic blisters.



Fibrinous exudate contains large amounts of fibrin as a result of activation of the coagulation system. When a fibrinous exudate occurs on a serosal surface, such as the pleura or pericardium, it is referred to as “fibrinous pleuritis” or “fibrinous pericarditis.”Purulent exudate or effusion contains prominent cellular components. It is frequently associated with pathological conditions such as pyogenic bacterial infections, in which the predominant cell type is the polymorphonuclear neutrophil (PMN).

Plasma-Derived MediatorsOf Inflammation

Cell- and plasma-derived mediators work in concert to activate cells by binding specific receptors, (2) Recruiting cells to sites of injury. (3) stimulating the release of additional soluble mediators.


Plasma contains the elements of three major enzyme cascades, These interrelated systems include The coagulation cascade and fibrinolytic system, (2) Kinin generation. (3) the complement system

Hageman Factor is a Key Source of VasoactiveMediators(clotting factor XII)

generated within the plasma and is activated by exposure to negatively charged surfaces such as basement membranes, proteolytic enzymes, bacterial lipopolysaccharides, and foreign materials.

Kinins Amplify the Inflammatory Response

Kinins are potent inflammatory agents formed in plasma and tissue by the action of serine protease kallikreins on specific plasma glycoproteins termed kininogens.Kinins amplify the inflammatoryresponse by stimulating local tissue cells and inflammatory cells to generate additional mediators, including prostanoids, cytokines (especially tumor necrosis factor-a[TNF-a] and interleukins), and nitric oxide (NO•).Kinins are rapidly degraded to inactive products by kininases and, therefore, have rapid and short-lived functions.

Complement is Activated Through ThreePathways to Form the Membrane AttackComplex (MAC)

The complement system is a group of proteins found in plasma and on cell surfaces, whose primary function is defense against microbes. The physiological activities of the complement system include: defense against pyogenic bacterial infection by opsonization, chemotaxis, activation of leukocytes and lysis of bacteria and cells. bridging innate and adaptive immunity for defense against microbial agents by augmenting antibody responses and enhancing immunological memory. disposal of immune products and products of inflammatory injury by clearance of immune complexes from tissues and removal of apoptotic cells.


The endpoint of complement activation is formation of the MAC and cell lysis. The cleavage products generated at each step of the way catalyze the next step in the cascade and have additional properties that render them important inflammatory molecules. Anaphylatoxins (C3a, C4a, C5a): These proinflammatory molecules mediate smooth-muscle contraction and increase vascular permeability. Opsonins (C3b, iC3b): Bacterial opsonization is the process by which a specific molecule (e.g., IgG or C3b) binds to the surface of the bacterium. The process enhances phagocytosis by enabling receptors on phagocytic cell membranes to recognize and bind the opsonized bacterium.



Proinflammatory molecules (MAC, C5a): These chemotactic factors also activate leukocytes and tissue cells to generate oxidants and cytokines and induce degranulation of mast cells and basophils.


The complement system is activated by three convergent pathways termed classical, mannose-binding lectin (MBL), and alternative pathways

The Classical Pathway

Activators include antigen-antibody (Ag-Ab) complexes, products of bacteria and viruses, proteases, urate crystals, apoptotic cells, and polyanions (polynucleotides). Ag-Ab complexes activate C1, initiating a cascade that leads to formation of the MAC.

The Mannose-Binding Pathway

It is initiated by the binding of microbes bearing terminal mannose groups to mannose-binding lectin, a member of the family of calcium-dependent lectins, termed the collectins. This multifunctional acute-phase protein has properties similar to those of (IgM) antibody (it binds to a wide range of oligosaccharide structures), IgG (it interacts with phagocytic receptors), and C1q. This last property enables it to interact with either C1r-C1s or with a serine protease called (MBL-associated serine protease) to activate complement

Alternative Pathway

initiated by derivative products of microorganisms, such as endotoxin (from bacterial cell surfaces), zymosan (yeast cell walls), polysaccharides , viruses, tumor cells, and foreign materials. Activation of the alternative pathway occurs at the level of C3 activation to produce small amounts of C3b. which become covalently bound to carbohydrates and proteins on microbial cell surfaces.

Cell-Derived MediatorsOf Inflammation

Circulating platelets, basophils, PMNs, endothelial cells, monocyte/macrophages, tissue mast cells, and the injured tissue itself are all potential cellular sources of vasoactive mediators.


Mediators are (1) derived from metabolism of phospholipids and arachidonic acid (e.g., prostaglandins, thromboxanes, leukotrienes, lipoxins, platelet-activating factor [PAF]).(2) preformed and stored in cytoplasmic granules (e.g., histamine, serotonin, lysosomal hydrolases).(3) derived from altered production of normal regulators of vascular function (e.g., NO•).

Cytokines are Cell-Derived Inflammatory Hormones

Cytokines constitute a group of low-molecular-weight hormone-like proteins secreted by cells. Many cytokines are produced at sites of inflammation, including interleukins, growth factors, colony-stimulating factors, interferons, and chemokines. Cytokines produced at sites of tissue injury regulate inflammatory responses, ranging from initial changes in vascular permeability to resolution and restoration of tissue integrity.


These molecules are inflammatory hormones that exhibit autocrine (affecting themselves), paracrine (affecting nearby cells), and endocrine (affecting cells in other tissues) functions. Through production of cytokines, macrophages are pivotal in orchestrating tissue inflammatory responses.


Monokines: Cytokines generated by mononuclear phagocytes. Lymphokines: Cytokines generated by activated lymphocytes. Colony-stimulating factor: Cytokines produced by monocytes and macrophages that stimulate the growth of immature leukocytes in bone marrow. Interleukines: broad family of cytokines that are made by hematopoietic cells and act primarly on leukocytes. Chemokines: Cytokines that are share the ability to stimulate leukocytes movements and direct movement and are particulary important in inflammation.

Cells Of Inflammation

Leukocytes are the major cellular components of the inflammatory response and include neutrophils, T and B lymphocytes, monocytes, macrophages, eosinophils, mast cells, and basophils. Specific functions are associated with each of these cell types, but such functions overlap and vary as inflammation progresses. local tissue cells interact with one another and with inflammatory cells, in a continuous response to injury and infection.

Neutrophils are the Major Cellular Participant in Acute Inflammation

They are activated in response to phagocytic stimuli, cytokines, chemotactic mediators or antigen

Endothelial Cells Line Blood Vessels

Endothelial cells comprise a monolayer of cells lining blood vessels and help to separate intra- and extravascular spaces. They produce agents that maintain blood vessel patency and also vasodilators and vasoconstrictors that regulate vascular tone. Injury to a vessel wall interrupts the endothelial barrier and exposes a local procoagulant signal. Endothelial cells are gatekeepers in inflammatory cell recruitment: they can promote or inhibit tissue perfusion and the influx of inflammatory cells.



Inflammatory agents, such as bradykinin and histamine, endotoxin and cytokines, induce endothelial cells to reveal adhesion molecules that (1) anchor and activate leukocytes, (2) present major histocompatibility complex (MHC) class I and II molecules. (3) generate cytokines and important vasoactive and inflammatory mediators.

Monocyte/Macrophages are Importantin Acute and Chronic Inflammation

In response to inflammatory mediators, they accumulate at sites of acute inflammation where they ingest and process microbes. Monocyte/macrophages produce potent vasoactive mediators, including prostaglandins and leukotrienes, PAF, and inflammatory cytokines. These cells are especially important for maintaining chronic inflammation.

Mast Cells and Basophils are Importantin Allergic Hypersensitivity Reactions

Mast cell products play an important role in regulating vascular permeability and bronchial smooth muscle tone, especially in allergic hypersensitivity reactions. Granulated mast cells and basophils contain cell surface receptors for IgE.

Eosinophils are Important in DefenseAgainst Parasites

Eosinophils contain leukotrienes and PAF, as well as acid phosphatase and peroxidase. They express IgA receptors and exhibit large granules that contain eosinophil major basic protein, both of which are involved in defense against parasites.

Platelets Play a Role in Normal Hemostasis

Platelets play a primary role in normal hemostasis and in initiating and regulating clot formation. They are sources of inflammatory mediators, including potent vasoactive substances and growth factors that modulate mesenchymal cell proliferation. Platelets adhere, aggregate, and degranulate when they contact fibrillar collagen (e.g., after vascular injury that exposes extracellular matrix [ECM] proteins) or thrombin (after activation of the coagulation system).

The platelet is small (2 mm in diameter), lacks a nucleus, andcontains three distinct kinds of inclusions:• dense granules, rich in serotonin, histamine, calciumand adenosine diphosphate• a granules, containing fibrinogen, coagulation proteins,platelet-derived growth factor, and other peptides andproteins• lysosomes, which sequester acid hydrolases

SYSTEMIC EFFECTS OF ACUTE INFLAMMATION

Fever‘Endogenous pyrogens’ produced: IL1 and TNFaIL1 - prostaglandins in hypothalamushence aspirin etc. reduce feverLeukocytosisIL1 and TNFa produce an accelerated release from marrowMacrophages, T lymphocytes produce colony-stimulating factorsBacterial infections - neutrophils, viral - lymphocytesClinically useful


SYSTEMIC EFFECTS OF ACUTE INFLAMMATION
Acute phase responseDecreased appetite, altered sleep patterns and changes in plasma concentrations of:Acute phase proteins:C-reactive protein (CRP) (Clinically useful)1 antitrypsinHaptoglobinFibrinogenSerum amyloid A protein

PROBLEMS CAUSED BY ACUTE INFLAMMATION

LocalSwelling: Blockage of tubes, e.g. bile duct, intestineExudate: Compression e.g. cardiac tamponadeLoss of fluid e.g. burnsPain & loss of function - especially if prolonged‘Bystander effect’ exacerbates damage, may initiate autoimmunity

PROBLEMS CAUSED BY ACUTE INFLAMMATION

Systemic Acute phase response Spread of micro-organisms and toxins SHOCK

Lobar pneumonia

Alveolar walls
Alveolishould containAIR… Not EXUDATE!

Myocardial infarct - neutrophil infiltration

Dead myocytes
Neutrophils

Leukocyte exudation

Divided into 4 steps Margination, rolling, and adhesion to endothelium Diapedesis (trans-migration across the endothelium) Migration toward a chemotactic stimuli from the source of tissue injury. Phagocytosis

Acute inflammation has one of four outcomes:

Abscess formation Progression to chronic inflammation Resolution--tissue goes back to normal Repair--healing by scarring or fibrosis