Acute inflammation

Inflammation (cont.)

Leukocyte Recruitment In AcuteInflammation
One of the essential features of acute inflammation is accumulation of leukocytes, particularly PMNs, in affected tissues. Leukocytes adhere to vascular endothelium, where they become activated. They then flatten and migrate from the vasculature through the endothelial cell layer into surrounding tissue. In the extravascular tissue, PMNs ingest foreign material, microbes, and dead tissue.


Leukocyte Adhesion to Endothelium Results from Interaction of Complementary Adhesion Molecules
Leukocyte recruitment to the postcapillary venules begins with interaction of leukocytes with endothelial cell selectins, which are redistributed to endothelial cell surfaces during activation. This interaction, called tethering, slows leukocytes in the blood flow. Leukocytes then move along the vascular endothelial cell surface with a saltatory movement, termed rolling. PMNs become activated by proximity to the endothelium and by inflammatory mediators, and adhere strongly to intercellular adhesion molecules on the endothelium (leukocyte arrest).


As endothelial cells separate, leukocytes transmigrate through the vessel wall and, under the influence of chemotactic factors, leukocytes migrate through extravascular tissue to the site of injury. The events involved in leukocyte recruitment are regulated as follows: (1) Inflammatory mediators stimulate resident tissue cells, including vascular endothelial cells; (2) Adhesion molecules are expressed on vascular endothelial cell surfaces and bind to reciprocal molecules on the surfaces of circulating leukocytes. (3) Chemotactic factors attract leukocytes along a chemical gradient to the site of injury.


Adhesion Molecules Four molecular families of adhesion molecules are involved in leukocyte recruitment: selectins, addressins, integrins, and immunoglobulins.

Selectins

The selectin family includes P-selectin, E-selectin, and L-selectin, expressed on the surface of platelets, endothelial cells, and leukocytes. These molecules are induced by the cytokines (IL-1) and TNF.


P-selectin is preformed and stored within Weibel-Palade bodies of endothelial cells and a-granules of platelets. On stimulation with histamine, thrombin, or specific inflammatory cytokines, P-selectin is rapidly transported to the cell surface, where it binds to sialyl-Lewis X on leukocyte surfaces. Preformed P-selectin can be delivered quickly to the cell surface, allowing rapid adhesive interaction between endothelial cells and leukocytes.

E-selectin is not normally expressed on endothelial cell surfaces but is induced by inflammatory mediators, such as cytokines. E-selectin mediates adhesion of neutrophils, monocytes, and certain lymphocytes via binding to molecules that contain Lewis X.

Addressins

Vascular addressins are mucin-like glycoproteins possess sialyl-Lewis X, which binds the lectin domain of selectins. Addressins are expressed at leukocyte and endothelial surfaces. They regulate localization of subpopulations of leukocytes and are involved in lymphocyte activation.

Integrins

Chemokines, lipid mediators, and proinflammatory molecules activate cells to express the integrin family of adhesion molecules.They participate in cell–cell interactions and cell–ECM binding.Leukocyte integrins exist in a low-affinity state, but are converted to a high affinity state when these cells are activated.

Immunoglobulin Superfamily

Adhesion molecules of the immunoglobulin (Ig) superfamily include ICAM-1, ICAM-2, and VCAM-1, all of which interact with integrins on leukocytes to mediate recruitment. They are expressed at the surfaces of cytokine-stimulated endothelial cells and some leukocytes, as well as certain epithelial cells, such as pulmonary alveolar cells.

Recruitment of Leukocytes

Tethering, rolling, and firm adhesion are prerequisites for recruitment of leukocytes from the circulation into tissues. For a rolling cell to adhere, there must first be a selectin-dependent reduction in rolling velocity. The early increase in rolling depends on P-selectin, whereas cytokine-induced E-selectin initiates early adhesion. Integrin family members function cooperatively with selectins to facilitate rolling and subsequent firm adhesion of leukocytes.


Leukocyte integrin binding to the Ig superfamily of ligands expressed on vascular endothelium further retards leukocytes, increasing the length of exposure of each leukocyte to endothelium. At the same time, engagement of adhesion molecules activates intracellular signal transduction. As a result, leukocytes and vascular endothelial cells are further activated, with subsequent upregulation of L-selectin and integrin binding. The net result is firm adhesion.

Chemotactic Molecules Direct Neutrophilsto Sites of Injury

This is process by which leukocytes are attracted to and move toward the injury. Chemotataxis and other form of cellular migration are measured in an in vitro system that assesses the migration of cells from and upper chamber through a microporous member to a lower chamber filled with a chemoattractant. This process mediated by diffusible chemical agents, movement of leukocytes occur along chemical gradient.

Chemotactic factors for neutrophils, produced at site of injury: Products from bacteria. Complement component especially C5a. Arachidonic acid metabolites, especially leukotriene (LT), hydroxyeicosatetaeonic acid (HETE) and kallikrein. Chemokines.

Chemotactic factors for other cell types, including lymphocytes, basophils, and eosinophils are also produced at sites of tissue injury and may be secreted by activated endothelial cells, tissue parenchymal cells, or other inflammatory cells. They include PAF, transforming growth factor- b (TGF-b), neutrophilic cationic proteins, and lymphokines.

Leukocytes Traverse the Endothelial CellBarrier to Gain Access to the Tissue

Leukocytes adherent to the vascular endothelium emigrate by paracellular diapedesis, (i.e., passing between adjacent endothelial cells). Responding to chemokine gradients, neutrophils extend pseudopods and insinuate themselves between the cells and out of the vascular space.

endothelial cells are connected by tight junctions and adherens junctions. CD31 (platelet endothelial cell adhesion molecule) is expressed on endothelial cell surfaces and binds to itself to keep cells together. These junctions separate under the influence of inflammatory mediators, intracellular signals generated by adhesion molecule engagement, and signals from the adherent neutrophils. Neutrophils mobilize elastase to their pseudopod membranes, inducing endothelial cell retraction and separation at the advancing edge of the neutrophil.


Neutrophils also induce increases in intracellular calcium in endothelial cells, to which the endothelial cells respond by pulling apart. Neutrophils also migrate through endothelial cells by transcellular diapedesis. Instead of inducing endothelial cell retraction, PMNs may squeeze through small circular pores in endothelial cell cytoplasm.

In tissues that contain fenestrated microvessels, such as gastrointestinal mucosa and secretory glands, PMNs may traverse thin regions of endothelium, called fenestrae, without damaging endothelial cells. In nonfenestrated microvessels, PMNs may cross the endothelium using endothelial cell caveolae or pinocytotic vesicles, which form small, membrane-bound passageways across the cell.

Leukocyte Functions In AcuteInflammation

Leukocytes Phagocytose Microorganism and Tissue Debris. Many inflammatory cells (including monocytes, tissue macrophages, dendritic cells, and neutrophils) recognize, internalize and digest foreign material, microorganisms, or cellular debris by a process termed phagocytosis. The effector cells are phagocytes. The complex process involves a sequence of transmembrane and intracellular signaling events.



1. Recognition: Phagocytosis is initiated by recognition of particles by specific receptors on the surface of phagocytic cells Phagocytosis of most biological agents is enhanced by, if not dependent on, their coating (opsonization) with plasma components (opsonins), particularly immunoglobulins or C3b. Phagocytic cells possess specific opsonic receptors, including those for immunoglobulin and complement components. Many pathogens, however, have evolved mechanisms to evade phagocytosis by leukocytes. Polysaccharide capsules, protein A, protein M, or peptidoglycans around bacteria can prevent complement deposition or antigen recognition and receptor binding.


2. Signaling: Clumping of opsonins on bacterial surfaces causes Fcg receptors on phagocytes to cluster. Tyrosine kinases that associate with the Fcg receptor are required for signaling during phagocytosis.


3. Internalization: In the case of phagocytosis initiated viathe Fcg receptor, actin assembly occurs directly under the phagocytosed target. Polymerized actin filaments push the plasma membrane forward. The plasma membrane remodels to increase surface area and to form pseudopods surrounding the foreign material. The resulting phagocytic cup engulfs the foreign agent. The membrane then “zippers” around the opsonized particle to enclose it in a cytoplasmic vacuole called a phagosome

4. Digestion: The phagosome that contains the foreign material fuses with cytoplasmic lysosomes to form a phagolysosome, into which lysosomal enzymes are released. The acid pH within the phagolysosome activates these hydrolytic enzymes, which then degrade the phagocytosed material. Some microorganisms have evolved mechanisms for evading killing by neutrophils by preventing lysosomal degranulation or inhibiting neutrophil enzymes.


B. Neutrophil Enzymes are Required for Antimicrobial Defense and Debridement. Although PMNs are critical for degrading microbes and cell debris, they also contribute to tissue injury. The release of PMN granules at sites of injury is a double-edged sword. On the one hand, debridement of damaged tissue by proteolytic breakdown is beneficial. On the other hand, degradative enzymes can damage endothelial and epithelial cells, as well degrade connective tissue.

Neutrophil Granules

The enzymes required for degradation of microbes and tissue is generated and contained within PMN cytoplasmic granules. Primary, secondary, and tertiary granules in neutrophils are differentiated morphologically and biochemically: each granule has a unique spectrum of enzymes

Inflammatory Cells Have Oxidativeand Nonoxidative Bactericidal Activity

The bactericidal activity of PMNs and macrophages is mediated in part by production of ROS and in part by oxygen-independent mechanisms.


Bacterial Killing by Oxygen Species
Phagocytosis is accompanied by metabolic reactions in inflammatory cells that lead to production of several oxygen metabolites. These products are more reactive than oxygen itself and contribute to the killing of ingested bacteria


Superoxide Anion (O2) Phagocytosis activates a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in PMN cell membranes. Activation of this enzyme is enhanced by prior exposure of cells to a chemotactic stimulus. NADPH oxidase activation increases oxygen consumption and stimulates the hexose monophosphate shunt. Together, these cell responses are referred to as the respiratory burst.


H2O2: O2 is rapidly converted to H2O2 by superoxide dismutase at the cell surface and in phagolysosomes. Hypochlorous Acid (HOCl): a neutrophil product with a strong cationic charge, is secreted from granules during exocytosis.

NO•: Phagocytic cells and vascular endothelial cells produce NO• and its derivatives, which have diverse effects, both physiological and nonphysiological.

Monocytes, macrophages, and eosinophils also produce oxygen radicals, depending on their state of activation and the stimulus to which they are exposed. Production of ROS by these cells contributes to their bactericidal and fungicidal activity as well as their ability to kill certain parasites.

Nonoxidative Bacterial Killing

Phagocytes, particularly PMNs and monocytes/macrophages, have substantial antimicrobial activity, which is oxygen independent. This activity mainly involves preformed bactericidal proteins in cytoplasmic granules. These include lysosomal acid hydrolases and specialized noncatalytic proteins unique to inflammatory cells.


Lysosomal hydrolases: Neutrophil primary and secondary granules and lysosomes of mononuclear phagocytes contain hydrolases. Bactericidal/permeability-increasing protein: This cationic protein in PMN primary granules can kill many gram-negative bacteria but is not toxic to gram-positive bacteria or to eukaryotic cells



Defensins: kill an extensive variety of gram positive and gram-negative bacteria, fungi, and some enveloped viruses. Lactoferrin: Lactoferrin is an iron-binding glycoprotein in the secondary granules of neutrophils and in most body secretory fluids. It also facilitate oxidative killing of bacteria by enhancing •OH formation.

Lysozyme: This bactericidal enzyme is found in many tissues and body fluids, in primary and secondary granules of neutrophils, and in lysosomes of mononuclear phagocytes.

CHRONIC INFLAMMATION

DEFINITION:It is prolonged process in which, destruction, inflammation and healing proceeding together at the same time.It is inflammation and healing processes,Proceed side by side.Causes: the same causes of acute inflammation,e.G.MICRORGANISM,CHEMICAL,IMMUNOLGICAL ,physical…etc. These causes If persist lead to chronicity

Chronic inflammation

When acute inflammation does not resolve or becomes disordered, chronic inflammation occurs. Inflammatory cells persist, stroma responds by becoming hyperplastic, and tissue destruction and scarring lead to organ dysfunction.

CAUSES

Microorganism like Tuberculosis,actinomycosis,even staphylococci cause granulomatous inflammation in patient with polymorph dysfunction. Foreign body causing chronic inflammation like silica, asbestos. Immunological cause like hypersensitivity angitis,contact dermatitis,rheumatoid arthritis,etc.


Acute and chronic inflammation are ends of a dynamic continuum with overlapping morphological features: (1) Inflammation with continued recruitment of chronic inflammatory cells is followed by (2) tissue injury due to prolongation of the inflammatory response, and (3) An often-disordered attempt to restore tissue integrity. The events leading to an amplified inflammatory response resemble those of acute inflammation in a number of aspects.


Specific triggers, microbial products or injury, initiate the response. Chemical mediators direct recruitment, activation, and interaction of inflammatory cells. Activation of coagulation and complement cascades generate small peptides that function to prolong the inflammatory response. Cytokines, specifically IL-6, regulate a switch in chemokines, such that mononuclear cells are directed to the site. Other cytokines (e.g., IFN-g) then promote macrophage proliferation and activation.


Inflammatory cells are recruited from the blood. Interactions between lymphocytes, macrophages, dendritic cells, and fibroblasts generate antigen-specific responses. Stromal cell activation and extracellular matrix remodeling occur, both of which affect the cellular immune response. Varying degrees of fibrosis may result, depending on the extent of tissue injury and persistence of the pathological stimulus and inflammatory response.



Chronic inflammation is not synonymous with chronic infection, but if the inflammatory response to infectious agents, including bacteria, viruses and notably parasites, cannot eliminate the organism, infection may persist. Chronic inflammation may also be associated with a variety of noninfectious disease states including:


Trauma: Extensive tissue damage releases mediators capable of inducing an extended inflammatory response. Cancer: Chronic inflammatory cells, especially macrophages and T lymphocytes, may be the morphological expression of an immune response to malignant cells. Chemotherapy may suppress normal inflammatory responses, increasing susceptibility to infection.

Immune factors: Many autoimmune diseases including rheumatoid arthritis, chronic thyroiditis, and primary biliary cirrhosis are characterized by chronic inflammatory responses in affected tissues. This may be associated with activation of antibody-dependent and cell-mediated immune mechanisms, such autoimmune responses may account for injury in affected organ.


Healing: repair ®eneration. Repair: it is a form of healing, when the lost tissue or damaged tissue replaced by fibrous tissue, as a result of fibroblast and Endothelial cells activity producing granulation tissue(capillary buds + fibroblast -collagen fibers),then granulation tissue fibrous tissue. Excessive fibrous tissue produce cicatrization and its bad effects-deformity.Cardiac muscle,deep skin burn, or glial scar in CNS.

CHRONIC INFLAMMATION

CHRONIC DISCHARGING SINUS
CHRONIC DENTAL ABSCESS

GRANULATION TISSUE FORMATION

GRANULATION TISSUE
RED & GRANULAR VASCULAR TISSUE
VASCULAR EASILY BLEEDS TISSUE

DEEP BURN WITH HEALING BY REPAIR

SCAR TISSUE WITH CICATRISATION
SCAR WITH CICATRISATION AND CONTRACTURE

GASTRIC ULCER

CHRONIC INFLAMMATION
HEALING WITH SCARING

Chronic Inflammation(Tissue destruction-Pancreas)

Chronic Inflammation (Fibrosis-pancreas)


REGENERATION: REPLACEMENT OF DAMAGED OR LOST TISSUE BY THE SAME TISSUE AS A RESULT OF CELL DIVISION OF THE SAME TISSUE .e.g. SUPERFICIAL SKIN BURN, HEPATITIS,FRACTURE BONES.

SUPERFICIAL BURN--REGENERATION

REVISION OF SOME TERMS

ORGANISATION :CONVERSION OF FIBRIN IN INFLAMMATION IN TO GRANULATION TISSUE= (CAPILLARY BUDS + FIBROBLASTS) . GRANULATION TISSUE =CAPILLARY BUDS +FIBROBLASTS WHICH LEADS TO FIBROUS TISSUE FORMATION DURING HEALING PROCESS . GRANULOMA :AGGRIGATION OF MACROPHAGE,WHICH EITHER DIFFUSE ,DIFFUSE GRANULOMA OR MASS LIKE CALLED TUBERCULOID GRANULOMA .

Granulomatous Inflammation

Granuloma formation is a protective response to chronic infection (fungal infections, tuberculosis, leprosy, schistosomiasis) or the presence of foreign material (e.g., suture). It prevents dissemination and restricts inflammation due to exogenous substances that are not effectively digested during the acute response, thereby protecting the host tissues.


Some autoimmune diseases (e.g., rheumatoid arthritis, Crohn disease, and sarcoidosis [a mysterious disease of unknown etiology]) are also associated with granulomas. The principal cells involved in granulomatous inflammation are macrophages and lymphocytes. Macrophages are mobile cells that continuously migrate through the extravascular connective tissues. After amassing substances that they cannot digest, macrophages lose their motility, accumulate at the site of injury, and undergo transformation into nodular collections of pale, epithelioid cells, creating a granuloma


Multinucleated giant cells are formed by the cytoplasmic fusion of macrophages. When the nuclei of such giant cells are arranged around the periphery of the cell in a horseshoe pattern, the cell is called a Langhans giant cell. If a foreign agent (e.g., silica or a Histoplasma spore) or other indigestible material is identified within the cytoplasm of a multinucleated giant cell, it is termed a foreign body giant cell. Granulomas are further classified histopathologically by the presence or absence of necrosis.


Certain infectious agents such as Mycobacterium tuberculosis characteristically produce caseating granulomas, the necrotic centers of which are filled with an amorphous mixture of debris and dead microorganisms and cells. Other diseases such as sarcoidosis are characterized by granulomas that lack necrosis.


T.B. CASEATION—COAGULATIVE NECROSIS WITH PRODUCTION OF CHEESY MATERIAL CASEATING LYMPH NODE
CASAETION –LUNG +L.N.


HORSE SHOE NUCLEI ARRANGEMENTLANGHAN,S GIANT CELL FOREIGHN BODY GIANT CELL

CRHON,S DISEASE

CRHON,S AS EXAMPLE OF CHRONIC GRANULOMATOUS NON-CASEATING INFLAMMATION
NON-CASEATING TUBERCULOID GRANULOMA

Chronic Granulomatous Inflammation

Chronic Granulomatous Inflammation

Chronic Granulomatous Inflammation

GIANT CELL ENGULFING BACTERIA