Inflammation PDF

INFLAMMATION ETTY HARY KUSUMASTUTI, DR. SP. PA (K), FIAC  TOPICS DEFINITION COUSES OF INFLAMMATION RECOGNITATION OF MICROBES AND DAMAGED CELLS ACUTE INFLAMMATION MEDIATORS OF INFLAMMATION MORPHOLOGIC PATTERN OF ACUTE INFLAMMATION OUTCOMES OF A...

INFLAMMATION ETTY HARY KUSUMASTUTI, DR. SP. PA (K), FIAC  TOPICS DEFINITION COUSES OF INFLAMMATION RECOGNITATION OF MICROBES AND DAMAGED CELLS ACUTE INFLAMMATION MEDIATORS OF INFLAMMATION MORPHOLOGIC PATTERN OF ACUTE INFLAMMATION OUTCOMES OF ACUTE INFLAMMATION CHRONIC INFLAMMATION SYSTEMIC EFFECTS OF INFLAMMATION  DEFINITION INFLAMMATION IS A RESPONSE OF VASCULARIZED TISSUES TO INFECTIONS AND TISSUE DAMAGE THAT BRINGS CELLS AND MOLECULES OF HOST DEFENSE FROM THE CIRCULATION TO THE SITES WHERE THEY ARE NEEDED, TO ELIMINATE THE OFFENDING AGENTS.  ALTHOUGH IN COMMON MEDICAL AND LAY PARLANCE, INFLAMMATION SUGGESTS A HARMFUL REACTION, IT IS ACTUALLY A PROTECTIVE RESPONSE THAT IS ESSENTIAL FOR SURVIVAL. WITHOUT INFLAMMATION, INFECTIONS WOULD GO UNCHECKED, WOUNDS WOULD NEVER HEAL, AND INJURED TISSUES MIGHT REMAIN PERMANENT FESTERING SORES. SEQUENCE OF EVENTS IN AN INFLAMMATORY REACTION. MACROPHAGES AND OTHER CELLS IN TISSUES RECOGNIZE MICROBES AND DAMAGED CELLS AND LIBERATE MEDIATORS, WHICH TRIGGER THE VASCULAR AND CELLULAR REACTIONS OF INFLAMMATION. THE TYPICAL INFLAMMATORY REACTION DEVELOPS THROUGH A SERIES OF SEQUENTIAL STEPS: 1. THE OFFENDING AGENT, WHICH IS LOCATED IN EXTRAVASCULAR TISSUES, IS RECOGNIZED BY HOST CELLS AND MOLECULES. 2. LEUKOCYTES AND PLASMA PROTEINS ARE RECRUITED FROM THE CIRCULATION TO THE SITE WHERE THE OFFENDING AGENT IS LOCATED. 3. THE LEUKOCYTES AND PROTEINS ARE ACTIVATED AND WORK TOGETHER TO DESTROY AND ELIMINATE THE OFFENDING SUBSTANCE. 4. THE REACTION IS CONTROLLED AND TERMINATED. 5. THE DAMAGED TISSUE IS REPAIRED. INFLAMMATION MAY BE OF TWO TYPES: ACUTE INFLAMMATION CHRONIC INFLAMMATION ACUTE INFLAMMATION: THE INITIAL, RAPID RESPONSE TO INFECTIONS AND TISSUE DAMAGE. TYPICALLY OF ACUTE INFLAMMATION: DEVELOPS WITHIN MINUTES OR HOURS SHORT DURATION, LASTING FOR SEVERAL HOURS OR A FEW DAYS. MAIN CHARACTERISTICS ARE THE EXUDATION OF FLUID AND PLASMA PROTEINS (EDEMA) EMIGRATION OF LEUKOCYTES, PREDOMINANTLY NEUTROPHILS (POLYMORPHONUCLEAR LEUKOCYTES). WHEN ACUTE INFLAMMATION ACHIEVES ITS DESIRED GOAL OF ELIMINATING THE OFFENDERS, THE REACTION SUBSIDES AND RESIDUAL INJURY IS REPAIRED CHRONIC INFLAMMATION IF THE INITIAL RESPONSE FAILS TO CLEAR THE STIMULUS, THE REACTION PROGRESSES TO A PROTRACTED TYPE OF INFLAMMATION TYPICALLY CHRONIC INFLAMMATION: LONGER DURATION ASSOCIATED WITH MORE TISSUE DESTRUCTION THE PRESENCE OF LYMPHOCYTES AND MACROPHAGES THE PROLIFERATION OF BLOOD VESSELS, AND FIBROSIS.  FEATURES OF ACUTE AND CHRONIC INFLAMMATION FEATUR ACUTE CHRONIC Onset Fast: minutes or hours Slow: days Cellular infiltrate Mainly neutrophils Monocytes/ macrophages and lymphocytes Tissue injury, fibrosis Usually mild and self-limited May be severe and progressive Local and systemic signs Prominent Less  Neutrophil (Polimorphonuclear leukocyte) Macrophage Monocyt e THE CLINICAL MANIFESTATIONS OF INFLAMMATION, OFTEN CALLED ITS CARDINAL SIGNS: 1. HEAT (CALOR) 2. REDNESS (RUBOR) 3. SWELLING (TUMOR) 4. PAIN (DOLOR) 5. LOSS OF FUNCTION (FUNCTIO LAESA). THE FIRST FOUR OF THESE WERE DESCRIBED MORE THAN 2000 YEARS AGO BY A ROMAN ENCYCLOPEDIST NAMED CELSUS, WHO WROTE THE THEN-FAMOUS TEXT DE MEDICINA. THE FIFTH WAS ADDED IN THE LATE 19TH CENTURY BY RUDOLF VIRCHOW, KNOWN AS THE “FATHER OF MODERN PATHOLOGY.” THESE MANIFESTATIONS OCCUR AS CONSEQUENCES OF THE VASCULAR CHANGES AND LEUKOCYTE RECRUITMENT AND ACTIVATION. DISORDERS CAUSED BY INFLAMMATORY REACTIONS  CAUSES OF INFLAMMATION INFLAMMATORY REACTIONS MAY BE TRIGGERED BY A VARIETY OF STIMULI: INFECTIONS TISSUE NECROSIS FOREIGN BODIES IMMUNE REACTIONS  INFECTIONS BACTERIAL, VIRAL, FUNGAL, PARASITIC INFECTION AND MICROBIAL TOXINS ARE AMONG THE MOST COMMON AND MEDICALLY IMPORTANT CAUSES OF INFLAMMATION.  TISSUE NECROSIS ELICITS INFLAMMATION REGARDLESS OF THE CAUSE OF CELL DEATH, WHICH MAY INCLUDE: ISCHEMIA (REDUCED BLOOD FLOW, THE CAUSE OF MYOCARDIAL INFARCTION) TRAUMA PHYSICAL INJURY (E.G., THERMAL INJURY, AS IN BURNS OR FROSTBITE; IRRADIATION) CHEMICAL INJURY (E.G., EXPOSURE TO SOME ENVIRONMENTAL CHEMICALS) SEVERAL MOLECULES RELEASED FROM NECROTIC CELLS ARE KNOWN TO TRIGGER INFLAMMATION.  FOREIGN BODIES SUCH AS SPLINTERS, DIRT, SUTURES, MAY ELICIT INFLAMMATION BY THEMSELVES OR BECAUSE THEY CAUSE TRAUMATIC TISSUE INJURY OR CARRY MICROBES. SOME ENDOGENOUS SUBSTANCES, STIMULATE POTENTIALLY HARMFUL INFLAMMATION IF LARGE AMOUNTS ARE DEPOSITED IN TISSUES; SUCH SUBSTANCES INCLUDE URATE CRYSTALS (IN THE DISEASE GOUT), AND CHOLESTEROL CRYSTALS (IN ATHEROSCLEROSIS)  IMMUNE REACTIONS ALSO CALLED HYPERSENSITIVITY, ARE REACTIONS IN WHICH THE NORMALLY PROTECTIVE IMMUNE SYSTEM DAMAGES THE INDIVIDUAL’S OWN TISSUES. THE INJURIOUS IMMUNE RESPONSES MAY BE DIRECTED AGAINST SELF ANTIGENS, CAUSING AUTOIMMUNE DISEASES. INAPPROPRIATE REACTIONS AGAINST ENVIRONMENTAL SUBSTANCES, AS IN ALLERGIES, OR AGAINST MICROBES.  RECOGNITION OF MICROBES AND DAMAGED CELLS THE FIRST STEP IN INFLAMMATORY RESPONSES IS THE RECOGNITION OF MICROBES AND NECROTIC CELLS BY CELLULAR RECEPTORS AND CIRCULATING PROTEINS. THE CELLS AND RECEPTORS THAT RECOGNIZE INVADERS ARE CRITICAL FOR SURVIVAL. RECOGNITION OF MICROBES AND DAMAGED CELLS: CELLULAR RECEPTORS FOR MICROBES. SENSORS OF CELL DAMAGE. CIRCULATING PROTEINS. CELLULAR RECEPTORS FOR MICROBES PHAGOCYTES, DENDRITIC CELLS (CELLS IN EPITHELIA AND ALL TISSUES WHOSE FUNCTION IS TO CAPTURE MICROBES), AND MANY OTHER CELLS EXPRESS RECEPTORS THAT DETECT THE PRESENCE OF INFECTIOUS PATHOGENS. THE BEST DEFINED OF THESE RECEPTORS BELONG TO THE FAMILY OF TOLL-LIKE RECEPTORS (TLR). TLR ARE LOCATED IN PLASMA MEMBRANES AND ENDOSOMES, SO THEY ARE ABLE TO DETECT EXTRACELLULAR AND INGESTED MICROBES. OTHER MICROBIAL SENSORS ARE PRESENT IN THE CYTOPLASM OF CELLS.  TLR RECOGNIZE MOTIFS COMMON TO MANY MICROBES, OFTEN CALLED PATHOGEN- ASSOCIATED MOLECULAR PATTERNS (PAMPS). RECOGNITION OF MICROBES BY THESE RECEPTORS STIMULATES THE PRODUCTION AND EXPRESSION OF A NUMBER OF SECRETED AND MEMBRANE PROTEINS. THESE PROTEINS INCLUDE CYTOKINES THAT INDUCE INFLAMMATION, ANTI-VIRAL CYTOKINES (INTERFERONS), AND CYTOKINES MEMBRANE PROTEINS THAT PROMOTE LYMPHOCYTE ACTIVATION AND EVEN MORE POTENT IMMUNE RESPONSES SENSORS OF CELL DAMAGE. ALL CELLS HAVE CYTOSOLIC RECEPTORS THAT RECOGNIZE MOLECULES THAT ARE LIBERATED OR ALTERED AS A CONSEQUENCE OF CELL DAMAGE, AND ARE HENCE APPROPRIATELY CALLED DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS). THESE MOLECULES INCLUDE URIC ACID (A PRODUCT OF DNA BREAKDOWN), ATP (RELEASED FROM DAMAGED MITOCHONDRIA), REDUCED INTRACELLULAR K+ CONCENTRATIONS (REFLECTING LOSS OF IONS BECAUSE OF PLASMA MEMBRANE INJURY), DNA (WHEN IT IS RELEASED INTO THE CYTOPLASM AND NOT SEQUESTERED IN NUCLEI, AS IT SHOULD BE NORMALLY), AND MANY OTHERS.  THE RECEPTORS ACTIVATE A MULTIPROTEIN CYTOSOLIC COMPLEX CALLED THE INFLAMMASOME, WHICH INDUCES THE PRODUCTION OF THE CYTOKINE INTERLEUKIN-1 (IL-1). IL-1 RECRUITS LEUKOCYTES AND THUS INDUCES INFLAMMATION. THE INFLAMMASOME ALSO HAS BEEN IMPLICATED IN INFLAMMATORY REACTIONS TO URATE CRYSTALS (THE CAUSE OF GOUT), CHOLESTEROL CRYSTALS (IN ATHEROSCLEROSIS), LIPIDS (IN METABOLIC SYNDROME AND OBESITY-ASSOCIATED DIABETES), AND AMYLOID DEPOSITS IN THE BRAIN (IN ALZHEIMER DISEASE). CIRCULATING PROTEINS. SEVERAL PLASMA PROTEINS RECOGNIZE MICROBES AND FUNCTION TO DESTROY BLOOD-BORNE MICROBES AND TO STIMULATE INFLAMMATION AT TISSUE SITES OF INFECTION. THE COMPLEMENT SYSTEM REACTS AGAINST MICROBES AND PRODUCES MEDIATORS OF INFLAMMATION. A CIRCULATING PROTEIN CALLED MANNOSE-BINDING LECTIN RECOGNIZES MICROBIAL SUGARS AND PROMOTES INGESTION OF MICROBES AND ACTIVATION OF THE COMPLEMENT SYSTEM. OTHER PROTEINS CALLED COLLECTINS ALSO BIND TO MICROBES AND PROMOTE THEIR PHAGOCYTOSIS.  ACUTE INFLAMMATION ACUTE INFLAMMATION HAS THREE MAJOR COMPONENTS: 1. DILATION OF SMALL VESSELS, LEADING TO AN INCREASE IN BLOOD FLOW. 2. INCREASED PERMEABILITY OF THE MICROVASCULATURE, ENABLING PLASMA PROTEINS AND LEUKOCYTES TO LEAVE THE CIRCULATION. 3. EMIGRATION OF THE LEUKOCYTES FROM THE MICROCIRCULATION, THEIR ACCUMULATION IN THE FOCUS OF INJURY, AND THEIR ACTIVATION TO ELIMINATE THE OFFENDING AGENT REACTIONS OF BLOOD VESSELS IN ACUTE INFLAMMATION THE VASCULAR REACTIONS OF ACUTE INFLAMMATION CONSIST OF: CHANGES IN THE FLOW OF BLOOD THE PERMEABILITY OF VESSELS BOTH DESIGNED TO MAXIMIZE THE MOVEMENT OF PLASMA PROTEINS AND LEUKOCYTES OUT OF THE CIRCULATION AND INTO THE SITE OF INFECTION OR INJURY → EXUDATION  EXUDATE IS AN EXTRAVASCULAR FLUID THAT HAS A HIGH PROTEIN CONCENTRATION AND CONTAINS CELLULAR DEBRIS. ITS PRESENCE IMPLIES THAT THERE IS AN INCREASE IN THE PERMEABILITY OF SMALL BLOOD VESSELS, TYPICALLY DURING AN INFLAMMATORY REACTION. TRANSUDATE IS A FLUID WITH LOW PROTEIN CONTENT, LITTLE OR NO CELLULAR MATERIAL, AND LOW SPECIFIC GRAVITY. IT IS ESSENTIALLY AN ULTRAFILTRATE OF BLOOD PLASMA THAT IS PRODUCED AS A RESULT OF OSMOTIC OR HYDROSTATIC IMBALANCE ACROSS VESSELS WITH NORMAL VASCULAR PERMEABILITY. CHANGES IN VASCULAR FLOW AND CALIBER CHANGES IN VASCULAR FLOW AND CALIBER BEGIN EARLY AFTER INJURY, AND CONSIST OF THE FOLLOWING: VASODILATION IS INDUCED BY THE ACTION OF SEVERAL MEDIATORS, NOTABLY HISTAMINE, ON VASCULAR SMOOTH MUSCLE. IT IS ONE OF THE EARLIEST MANIFESTATIONS OF ACUTE INFLAMMATION. VASODILATION FIRST INVOLVES THE ARTERIOLES AND THEN LEADS TO THE OPENING OF NEW CAPILLARY BEDS IN THE AREA. THE RESULT IS INCREASED BLOOD FLOW, WHICH IS THE CAUSE OF HEAT AND REDNESS (ERYTHEMA) AT THE SITE OF INFLAMMATION. INCREASED PERMEABILITY OF THE MICROVASCULATURE, WITH THE OUTPOURING OF PROTEIN-RICH FLUID (AN EXUDATE) INTO THE EXTRAVASCULAR TISSUES. THE LOSS OF FLUID AND INCREASED VESSEL DIAMETER LEAD TO SLOWER BLOOD FLOW, CONCENTRATION OF RED CELLS IN SMALL VESSELS, AND INCREASED VISCOSITY OF THE BLOOD. THESE CHANGES RESULT IN STASIS OF BLOOD FLOW, ENGORGEMENT OF SMALL VESSELS JAMMED WITH SLOWLY MOVING RED CELLS, SEEN HISTOLOGICALLY AS VASCULAR CONGESTION AND EXTERNALLY AS LOCALIZED REDNESS (ERYTHEMA) OF THE INVOLVED TISSUE. AS STASIS DEVELOPS, BLOOD LEUKOCYTES, PRINCIPALLY NEUTROPHILS, ACCUMULATE ALONG THE VASCULAR ENDOTHELIUM. AT THE SAME TIME ENDOTHELIAL CELLS ARE ACTIVATED BY MEDIATORS PRODUCED AT SITES OF INFECTION AND TISSUE DAMAGE, AND EXPRESS INCREASED LEVELS OF ADHESION MOLECULES. LEUKOCYTES THEN ADHERE TO THE ENDOTHELIUM, AND SOON AFTERWARD THEY MIGRATE THROUGH THE VASCULAR WALL INTO THE INTERSTITIAL TISSUE, IN A SEQUENCE INCREASED VASCULAR PERMEABILITY (VASCULAR LEAKAGE) SEVERAL MECHANISMS ARE RESPONSIBLE FOR INCREASED VASCULAR PERMEABILITY IN ACUTE INFLAMMATION, WHICH INCLUDE: RETRACTION OF ENDOTHELIAL CELLS ENDOTHELIAL INJURY INCREASED TRANSCYTOSIS RETRACTION OF ENDOTHELIAL CELLS THIS MECHANISM RESULTING IN OPENING OF INTER ENDOTHELIAL SPACES IS THE MOST COMMON MECHANISM OF VASCULAR LEAKAGE. IT IS ELICITED BY HISTAMINE, BRADYKININ, LEUKOTRIENES, AND OTHER CHEMICAL MEDIATORS. IT OCCURS RAPIDLY AFTER EXPOSURE TO THE MEDIATOR (WITHIN 15 TO 30 MINUTES) AND IS USUALLY SHORT-LIVED; HENCE, IT IS REFERRED TO AS THE IMMEDIATE TRANSIENT RESPONSE. THE MAIN SITES FOR THIS RAPID INCREASE IN VASCULAR PERMEABILITY ARE POST CAPILLARY VENULES. ENDOTHELIAL INJURY THIS MECHANISM RESULTING IN ENDOTHELIAL CELL NECROSIS AND DETACHMENT. DIRECT DAMAGE TO THE ENDOTHELIUM IS ENCOUNTERED IN SEVERE INJURIES, FOR EXAMPLE, IN BURNS, OR IS INDUCED BY THE ACTIONS OF MICROBES AND MICROBIAL TOXINS THAT TARGET ENDOTHELIAL CELLS. NEUTROPHILS THAT ADHERE TO THE ENDOTHELIUM DURING INFLAMMATION MAY ALSO INJURE THE ENDOTHELIAL CELLS AND THUS AMPLIFY THE REACTION. IN MOST INSTANCES LEAKAGE STARTS IMMEDIATELY AFTER INJURY AND IS SUSTAINED FOR SEVERAL HOURS UNTIL THE DAMAGED VESSELS ARE THROMBOSED OR REPAIRED. INCREASED TRANSCYTOSIS INCREASED TRANSPORT OF FLUIDS AND PROTEINS, CALLED TRANSCYTOSIS, THROUGH THE ENDOTHELIAL CELL. THIS PROCESS, DOCUMENTED IN EXPERIMENTAL MODELS, MAY INVOLVE INTRACELLULAR CHANNELS THAT OPEN IN RESPONSE TO CERTAIN FACTORS, SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), THAT PROMOTE VASCULAR LEAKAGE. ITS CONTRIBUTION TO THE VASCULAR PERMEABILITY SEEN IN ACUTE INFLAMMATION IN HUMANS IS UNCLEAR. RESPONSES OF LYMPHATIC VESSELS AND LYMPH NODES LYMPHATIC VESSELS ALSO PARTICIPATE IN ACUTE INFLAMMATION. THE SYSTEM OF LYMPHATICS AND LYMPH NODES FILTERS AND POLICES THE EXTRAVASCULAR FLUIDS. LYMPHATICS DRAIN THE SMALL AMOUNT OF EXTRAVASCULAR FLUID THAT SEEPS OUT OF CAPILLARIES UNDER NORMAL CIRCUMSTANCES. IN INFLAMMATION, LYMPH FLOW IS INCREASED TO HELP DRAIN EDEMA FLUID THAT ACCUMULATES BECAUSE OF INCREASED VASCULAR PERMEABILITY. IN ADDITION TO FLUID, LEUKOCYTES AND CELL DEBRIS, AS WELL AS MICROBES, MAY FIND THEIR WAY INTO LYMPH. LYMPHATIC VESSELS, LIKE BLOOD VESSELS, PROLIFERATE DURING INFLAMMATORY REACTIONS TO HANDLE THE INCREASED LOAD. THE LYMPHATICS MAY BECOME SECONDARILY INFLAMED (LYMPHANGITIS), AS MAY THE DRAINING LYMPH NODES (LYMPHADENITIS). INFLAMED LYMPH NODES ARE OFTEN ENLARGED BECAUSE OF INCREASED CELLULARITY. THIS CONSTELLATION OF PATHOLOGIC CHANGES IS TERMED REACTIVE, OR INFLAMMATORY, LYMPHADENITIS. LEUKOCYTE RECRUITMENT TO SITES OF INFLAMMATION LEUKOCYTES THAT ARE RECRUITED TO SITES OF INFLAMMATION PERFORM THE KEY FUNCTION OF ELIMINATING THE OFFENDING AGENTS. THE MOST IMPORTANT LEUKOCYTES IN TYPICAL INFLAMMATORY REACTIONS ARE THE ONES CAPABLE OF PHAGOCYTOSIS → NEUTROPHILS AND MACROPHAGES. PROPERTIES OF NEUTROPHILS AND MACROPHAGES LEUKOCYTE RECRUITMENT TO SITES OF INFLAMMATION LEUKOCYTE ADHESION TO ENDOTHELIUM LEUKOCYTE MIGRATION THROUGH ENDOTHELIUM CHEMOTAXIS OF LEUKOCYTES LEUKOCYTE ADHESION TO ENDOTHELIUM RED CELLS, BEING SMALLER, TEND TO MOVE FASTER THAN THE LARGER WHITE CELLS. AS A RESULT, RED CELLS ARE CONFINED TO THE CENTRAL AXIAL COLUMN, AND LEUKOCYTES ARE PUSHED OUT TOWARD THE WALL OF THE VESSEL, BUT THE FLOW PREVENTS THE CELLS FROM ATTACHING TO THE ENDOTHELIUM. AS THE BLOOD FLOW SLOWS EARLY IN INFLAMMATION (STASIS), HEMODYNAMIC CONDITIONS CHANGE (WALL SHEAR STRESS DECREASES), AND MORE WHITE CELLS ASSUME A PERIPHERAL POSITION ALONG THE ENDOTHELIAL SURFACE. THIS PROCESS OF LEUKOCYTE REDISTRIBUTION IS CALLED MARGINATION.  BY MOVING CLOSE TO THE VESSEL WALL, LEUKOCYTES ARE ABLE TO DETECT AND REACT TO CHANGES IN THE ENDOTHELIUM. IF THE ENDOTHELIAL CELLS ARE ACTIVATED BY CYTOKINES AND OTHER MEDIATORS PRODUCED LOCALLY, THEY EXPRESS ADHESION MOLECULES TO WHICH THE LEUKOCYTES ATTACH LOOSELY. THESE CELLS BIND AND DETACH AND THUS BEGIN TO TUMBLE ON THE ENDOTHELIAL SURFACE, A PROCESS CALLED ROLLING. THE CELLS FINALLY COME TO REST AT SOME POINT WHERE THEY ADHERE FIRMLY SELECTINS AN ADHESION MOLECULE MEDIATE THE INITIAL WEAK INTERACTIONS BETWEEN LEUKOCYTES AND ENDOTHELIUM. SELECTINS ARE RECEPTORS EXPRESSED ON LEUKOCYTES AND ENDOTHELIUM THAT CONTAIN AN EXTRACELLULAR DOMAIN THAT BINDS SUGARS. THE THREE MEMBERS OF THIS FAMILY ARE: E-SELECTIN (ALSO CALLED CD62E), EXPRESSED ON ENDOTHELIAL CELLS. P-SELECTIN (CD62P), PRESENT ON PLATELETS AND ENDOTHELIUM. L-SELECTIN (CD62L), FOUND ON THE SURFACE OF MOST LEUKOCYTES. THE LIGANDS FOR SELECTINS ARE SIALIC ACID-CONTAINING OLIGOSACCHARIDES BOUND TO GLYCOPROTEIN BACKBONES. THESE ADHESION MOLECULE ARE LOW-AFFINITY INTERACTIONS WITH A FAST OFF RATE, AND THEY ARE EASILY DISRUPTED BY THE FLOWING BLOOD. AS A RESULT, THE BOUND LEUKOCYTES BIND, DETACH, AND BIND AGAIN, AND THUS BEGIN TO ROLL ALONG THE ENDOTHELIAL SURFACE. INTEGRIN FIRM ADHESION OF LEUKOCYTES TO ENDOTHELIUM IS MEDIATED BY A FAMILY OF LEUKOCYTE SURFACE PROTEINS CALLED INTEGRINS. INTEGRINS ARE TRANSMEMBRANE TWO-CHAIN GLYCOPROTEINS THAT MEDIATE THE ADHESION OF LEUKOCYTES TO ENDOTHELIUM AND OF VARIOUS CELLS TO THE EXTRACELLULAR MATRIX. THEY ARE NORMALLY EXPRESSED ON LEUKOCYTE PLASMA MEMBRANES IN A LOW-AFFINITY FORM AND DO NOT ADHERE TO THEIR SPECIFIC LIGANDS UNTIL THE LEUKOCYTES ARE ACTIVATED BY CHEMOKINES. CHEMOKINES ARE CHEMOATTRACTANT CYTOKINES THAT ARE SECRETED BY MANY CELLS AT SITES OF INFLAMMATION. WHEN THE ROLLING LEUKOCYTES ENCOUNTER THE DISPLAYED CHEMOKINES, THE CELLS ARE ACTIVATED, AND THEIR INTEGRINS UNDERGO CONFORMATIONAL CHANGES AND CLUSTER TOGETHER, THUS CONVERTING TO A HIGH-AFFINITY FORM.  AT THE SAME TIME, OTHER CYTOKINES, NOTABLY TNF AND IL-1, ACTIVATE ENDOTHELIAL CELLS TO INCREASE THEIR EXPRESSION OF LIGANDS FOR INTEGRINS. THESE LIGANDS INCLUDE: INTERCELLULAR ADHESION MOLECULE-1 (ICAM-1), WHICH BINDS TO THE INTEGRINS LEUKOCYTE FUNCTION–ASSOCIATED ANTIGEN-1 (LFA-1) (ALSO CALLED CD11ACD18) AND MACROPHAGE-1 ANTIGEN (MAC-1) (CD11BCD18) VASCULAR CELL ADHESION MOLECULE-1 (VCAM-1), WHICH BINDS TO THE INTEGRIN VERY LATE ANTIGEN-4 (VLA-4) THE COMBINATION OF CYTOKINE-INDUCED EXPRESSION OF INTEGRIN LIGANDS ON THE ENDOTHELIUM AND INCREASED AFFINITY OF INTEGRINS ON THE LEUKOCYTES RESULTS IN FIRM INTEGRIN-MEDIATED BINDING OF THE LEUKOCYTES TO THE ENDOTHELIUM AT THE SITE OF INFLAMMATION → THE LEUKOCYTES STOP ROLLING, AND ENGAGEMENT OF INTEGRINS BY THEIR LIGANDS DELIVERS SIGNALS LEADING TO CYTOSKELETAL CHANGES THAT ARREST THE LEUKOCYTES AND FIRMLY ATTACH THEM TO THE ENDOTHELIUM. LEUKOCYTE MIGRATION THROUGH ENDOTHELIUM AFTER BEING ARRESTED ON THE ENDOTHELIAL SURFACE, LEUKOCYTES MIGRATE THROUGH THE VESSEL WALL PRIMARILY BY SQUEEZING BETWEEN CELLS AT INTERCELLULAR JUNCTIONS. THIS EXTRAVASATION OF LEUKOCYTES, CALLED TRANSMIGRATION, OCCURS MAINLY IN POSTCAPILLARY VENULES, THE SITE AT WHICH THERE IS MAXIMAL RETRACTION OF ENDOTHELIAL CELLS. LEUKOCYTES IS DRIVEN BY CHEMOKINES PRODUCED IN EXTRAVASCULAR TISSUES, WHICH STIMULATE LEUKOCYTES TO TRAVEL ALONG A CHEMICAL GRADIENT. PLATELET ENDOTHELIAL CELL ADHESION MOLECULE-1 (PECAM-1) (ALSO CALLED CD31), AN ADHESION MOLECULE OF THE IMMUNOGLOBULIN (IG) SUPERFAMILY EXPRESSED ON LEUKOCYTES AND ENDOTHELIAL CELLS, MEDIATES THE BINDING EVENTS NEEDED FOR LEUKOCYTES TO TRAVERSE THE ENDOTHELIUM. AFTER TRAVERSING THE ENDOTHELIUM, LEUKOCYTES PIERCE THE BASEMENT MEMBRANE, PROBABLY BY SECRETING COLLAGENASES, AND THEY ENTER THE EXTRAVASCULAR TISSUE. CHEMOTAXIS OF LEUKOCYTES LEUKOCYTES MOVE IN THE TISSUES TOWARD THE SITE OF INJURY BY A PROCESS CALLED CHEMOTAXIS, WHICH IS DEFINED AS LOCOMOTION ALONG A CHEMICAL GRADIENT. BOTH EXOGENOUS AND ENDOGENOUS SUBSTANCES CAN ACT AS CHEMOATTRACTANTS, INCLUDING THE FOLLOWING: BACTERIAL PRODUCTS, PARTICULARLY PEPTIDES WITH N-FORMYLMETHIONINE TERMINI CYTOKINES, ESPECIALLY THOSE OF THE CHEMOKINE FAMILY COMPONENTS OF THE COMPLEMENT SYSTEM, PARTICULARLY C5A PRODUCTS OF THE LIPOXYGENASE PATHWAY OF ARACHIDONIC ACID (AA) METABOLISM, PARTICULARLY LEUKOTRIENE B4 (LTB4)  CHEMOATTRACTANT ACT BY BINDING TO SEVEN TRANSMEMBRANE G PROTEIN-COUPLED RECEPTORS ON THE SURFACE OF LEUKOCYTES. SIGNALS INITIATED FROM THESE RECEPTORS ACTIVATE SECOND MESSENGERS THAT INDUCE POLYMERIZATION OF ACTIN, RESULTING LEUKOCYTE MOVEMENT BY EXTENDING FILOPODIA THAT PULL THE BACK OF THE CELL IN THE DIRECTION OF EXTENSION. THE NET RESULT IS THAT LEUKOCYTES MIGRATE TOWARD THE INFLAMMATORY STIMULUS IN THE DIRECTION OF THE LOCALLY PRODUCED CHEMOATTRACTANTS. THE NATURE OF THE LEUKOCYTE INFILTRATE VARIES WITH THE AGE OF THE INFLAMMATORY RESPONSE AND THE TYPE OF STIMULUS. IN MOST FORMS OF ACUTE INFLAMMATION, NEUTROPHILS PREDOMINATE IN THE INFLAMMATORY INFILTRATE DURING THE FIRST 6 TO 24 HOURS AND ARE GRADUALLY REPLACED BY MONOCYTE-DERIVED MACROPHAGES OVER 24 TO 48 HOURS AFTER ENTERING TISSUES, NEUTROPHILS ARE SHORT-LIVED; THEY UNDERGO APOPTOSIS AND DISAPPEAR WITHIN 24 TO 48 HOURS. MACROPHAGES NOT ONLY SURVIVE LONGER BUT ALSO MAY PROLIFERATE IN THE TISSUES, AND THUS THEY BECOME THE DOMINANT POPULATION IN PROLONGED INFLAMMATORY REACTIONS. PHAGOCYTOSIS AND CLEARANCE OF THE OFFENDING AGENT RECOGNITION OF MICROBES OR DEAD CELLS INDUCES SEVERAL RESPONSES IN LEUKOCYTES THAT ARE CALLED LEUKOCYTE ACTIVATION AFTER LEUKOCYTES (PARTICULARLY NEUTROPHILS AND MONOCYTES) HAVE BEEN RECRUITED TO A SITE OF INFECTION OR TISSUE INJURY THEY MUST BE ACTIVATED TO PERFORM THEIR FUNCTIONS. PHAGOCYTOSIS INVOLVES THREE SEQUENTIAL STEPS: RECOGNITION AND ATTACHMENT OF THE PARTICLE TO BE INGESTED BY THE LEUKOCYTE ENGULFMENT, WITH SUBSEQUENT FORMATION OF A PHAGOCYTIC VACUOLE KILLING OR DEGRADATION OF THE INGESTED MATERIAL RECOGNITION BY PHAGOCYTIC RECEPTORS. MANNOSE RECEPTORS, SCAVENGER RECEPTORS, AND RECEPTORS FOR VARIOUS OPSONINS BIND AND INGEST MICROBES. THE MACROPHAGE MANNOSE RECEPTOR IS A LECTIN THAT BINDS TERMINAL MANNOSE AND FUCOSE RESIDUES OF GLYCOPROTEINS AND GLYCOLIPIDS. THESE SUGARS ARE TYPICALLY PART OF MOLECULES FOUND ON MICROBIAL CELL WALLS. SCAVENGER RECEPTORS BIND AND INGEST LOW-DENSITY LIPOPROTEIN (LDL) PARTICLES AS WELL AS A VARIETY OF MICROBES. THE EFFICIENCY OF PHAGOCYTOSIS IS GREATLY ENHANCED WHEN MICROBES ARE OPSONIZED (COATED) BY SPECIFIC PROTEINS (OPSONINS). THE MAJOR OPSONINS: IMUNOGLOBULIN (IG)G ANTIBODIES C3B BREAKDOWN PRODUCT OF COMPLEMENT ACTIVATION CERTAIN PLASMA LECTINS. ENGULFMENT. AFTER A PARTICLE IS BOUND TO PHAGOCYTE RECEPTORS, EXTENSIONS OF THE CYTOPLASM (PSEUDOPODS) FLOW AROUND IT, AND THE PLASMA MEMBRANE PINCHES OFF TO FORM A CYTOSOLIC VESICLE (PHAGOSOME) THAT ENCLOSES THE PARTICLE. THE PHAGOSOME THEN FUSES WITH LYSOSOMES, RESULTING IN THE DISCHARGE OF LYSOSOMAL CONTENTS INTO THE PHAGOLYSOSOME KILLING OR DEGRADATION OF THE INGESTED MATERIAL THE KILLING OF MICROBES AND THE DESTRUCTION OF INGESTED MATERIALS ARE ACCOMPLISHED BY: REACTIVE OXYGEN SPECIES (ROS, ALSO CALLED REACTIVE OXYGEN INTERMEDIATES) REACTIVE NITROGEN SPECIES, MAINLY DERIVED FROM NITRIC OXIDE (NO) LYSOSOMAL ENZYMES ALL THESE KILLING MECHANISMS ARE NORMALLY SEQUESTERED IN LYSOSOMES, TO WHICH PHAGOCYTOSED MATERIALS ARE BROUGHT. THUS, POTENTIALLY HARMFUL SUBSTANCES ARE SEGREGATED FROM THE CELL’S CYTOPLASM AND NUCLEUS TO AVOID DAMAGE TO THE PHAGOCYTE WHILE IT IS PERFORMING ITS NORMAL FUNCTION. PHAGOCYTOSIS AND INTRACELLULAR DESTRUCTION OF MICROBES. (A) PHAGOCYTOSIS OF A PARTICLE (E.G., A BACTERIUM) INVOLVES BINDING TO RECEPTORS ON THE LEUKOCYTE MEMBRANE, ENGULFMENT, AND FUSION OF THE PHAGOCYTIC VACUOLES WITH LYSOSOMES. THIS IS FOLLOWED BY DESTRUCTION OF INGESTED PARTICLES WITHIN THE PHAGOLYSOSOMES BY LYSOSOMAL ENZYMES AND BY REACTIVE OXYGEN AND NITROGEN SPECIES. (B) IN ACTIVATED PHAGOCYTES, CYTOPLASMIC COMPONENTS OF THE PHAGOCYTE OXIDASE ENZYME ASSEMBLE IN THE MEMBRANE OF THE PHAGOSOME TO FORM THE ACTIVE ENZYME, WHICH CATALYZES THE CONVERSION OF OXYGEN INTO SUPEROXIDE ( O2 − ) AND H2O2. MYELOPEROXIDASE, PRESENT IN THE GRANULES OF NEUTROPHILS, CONVERTS H2O2 TO HYPOCHLORITE. (C) MICROBICIDAL REACTIVE OXYGEN SPECIES (ROS) AND NITRIC OXIDE (NO) KILL INGESTED MICROBES. DURING PHAGOCYTOSIS, GRANULE CONTENTS MAY BE RELEASED INTO EXTRACELLULAR TISSUES (NOT SHOWN). NEUTROPHIL EXTRACELLULAR TRAPS NEUTROPHIL EXTRACELLULAR TRAPS (NETS) ARE EXTRACELLULAR FIBRILLAR NETWORKS THAT CONCENTRATE ANTI-MICROBIAL SUBSTANCES AT SITES OF INFECTION AND PREVENT THE SPREAD OF THE MICROBES BY TRAPPING THEM IN THE FIBRILS. THEY ARE PRODUCED BY NEUTROPHILS IN RESPONSE TO INFECTIOUS PATHOGENS (MAINLY BACTERIA AND FUNGI) AND INFLAMMATORY MEDIATORS (E.G., CHEMOKINES, CYTOKINES, AND COMPLEMENT PROTEINS). THE EXTRACELLULAR TRAPS CONSIST OF A VISCOUS MESHWORK OF NUCLEAR CHROMATIN THAT BINDS AND CONCENTRATES GRANULE PROTEINS SUCH AS ANTI-MICROBIAL PEPTIDES AND ENZYMES. NETS PROVIDE AN ADDITIONAL MECHANISM OF KILLING MICROBES THAT DOES NOT INVOLVE PHAGOCYTOSIS. IN THE PROCESS OF NET FORMATION, THE NUCLEI OF THE NEUTROPHILS ARE LOST, LEADING TO THE DEATH OF THE CELLS, SOMETIMES CALLED NETOSIS, REPRESENTING A DISTINCTIVE FORM OF CELL DEATH AFFECTING NEUTROPHILS. NETS ALSO HAVE BEEN DETECTED IN THE BLOOD DURING SEPSIS. LEUKOCYTE-MEDIATED TISSUE INJURY LEUKOCYTES ARE IMPORTANT MEDIATORS OF INJURY TO NORMAL CELLS AND TISSUES UNDER SEVERAL CIRCUMSTANCES: AS PART OF A NORMAL DEFENSE REACTION AGAINST INFECTIOUS MICROBES, WHEN TISSUES AT OR NEAR THE SITE OF INFECTION SUFFER COLLATERAL DAMAGE. IN SOME INFECTIONS THAT ARE DIFFICULT TO ERADICATE, SUCH AS TUBERCULOSIS AND CERTAIN VIRAL DISEASES SUCH AS HEPATITIS, THE PROLONGED HOST RESPONSE CONTRIBUTES MORE TO THE PATHOLOGY THAN DOES THE MICROBE ITSELF. THE INFLAMMATORY RESPONSE IS INAPPROPRIATELY DIRECTED AGAINST HOST TISSUES → AUTOIMMUNE DISEASES. THE HOST “HYPER-REACTS” AGAINST USUALLY HARMLESS ENVIRONMENTAL SUBSTANCES → ALLERGIC DISEASES, DRUG REACTIONS. OTHER FUNCTIONAL RESPONSES OF ACTIVATED LEUKOCYTES IN ADDITION TO ELIMINATING MICROBES AND DEAD CELLS, ACTIVATED LEUKOCYTES PLAY SEVERAL OTHER ROLES IN HOST DEFENSE. OTHER FUNCTIONAL RESPONSE OF ACTIVATED MACROPHAGES ARE: PRODUCE CYTOKINES THAT CAN EITHER AMPLIFY OR LIMIT INFLAMMATORY REACTIONS PRODUCE GROWTH FACTORS THAT STIMULATE THE PROLIFERATION OF ENDOTHELIAL CELLS AND FIBROBLASTS SYNTHESIS OF COLLAGEN AND ENZYMES THAT REMODEL CONNECTIVE TISSUES.  TERMINATION OF THE ACUTE INFLAMMATORY RESPONSE THE MEDIATORS OF INFLAMMATION ARE PRODUCED IN RAPID BURSTS, ONLY AS LONG AS THE STIMULUS PERSISTS, HAVE SHORT HALF-LIVES, AND ARE DEGRADED AFTER THEIR RELEASE. NEUTROPHILS ALSO HAVE SHORT HALF-LIVES IN TISSUES AND DIE BY APOPTOSIS WITHIN HOURS TO A DAY OR TWO AFTER LEAVING THE BLOOD.  MEDIATORS OF INFLAMMATION THE MEDIATORS OF INFLAMMATION ARE THE SUBSTANCES THAT INITIATE AND REGULATE INFLAMMATORY REACTIONS. THE MOST IMPORTANT MEDIATORS OF ACUTE INFLAMMATION ARE: VASOACTIVE AMINES LIPID PRODUCTS (PROSTAGLANDINS AND LEUKOTRIENES) CYTOKINES (INCLUDING CHEMOKINES) PRODUCTS OF COMPLEMENT ACTIVATION  PRINCIPAL MEDIATORS OF INFLAMMATION Mediator Source Action Histamine Mast cells, basophils, platelets Vasodilation, increased vascular permeability, endothelial activation Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever Leukotriene Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion, and activation Cytokines (TNF, Macrophages, endothelial cells, Local: endothelial activation (expression of adhesion IL-1, IL-6) mast cells molecules). Systemic: fever, metabolic abnormalities, hypotension (shock) Chemokines Leukocytes, activated macrophages Chemotaxis, leukocyte activation Platelet-activating Leukocytes, mast cells Vasodilation, increased vascular permeability, leukocyte factor adhesion, chemotaxis, degranulation, oxidative burst Complement Plasma (produced in liver) Leukocyte chemotaxis and activation, direct target killing (membrane attack complex), vasodilation (mast cell stimulation) Kinins Plasma (produced in liver) Increased vascular permeability, smooth muscle contraction,  VASOACTIVE AMINES: HISTAMINE AND SEROTONIN THE TWO MAJOR VASOACTIVE AMINES, SO NAMED BECAUSE THEY HAVE IMPORTANT ACTIONS ON BLOOD VESSELS, ARE HISTAMINE AND SEROTONIN. HISTAMINE CAUSES DILATION OF ARTERIOLES AND INCREASES THE PERMEABILITY OF VENULES. SEROTONIN (5-HYDROXYTRYPTAMINE) IS A PREFORMED VASOACTIVE MEDIATOR PRESENT IN PLATELETS AND CERTAIN NEUROENDOCRINE CELLS, SUCH AS IN THE GASTROINTESTINAL TRACT, AND IN MAST CELLS IN RODENTS BUT NOT HUMANS. ARACHIDONIC ACID METABOLITES THE LIPID MEDIATORS PROSTAGLANDINS AND LEUKOTRIENES ARE PRODUCED FROM ARACHIDONIC ACID PRESENT IN MEMBRANE PHOSPHOLIPIDS, AND THEY STIMULATE VASCULAR AND CELLULAR REACTIONS IN ACUTE INFLAMMATION. PROSTAGLANDINS (PGS) ARE PRODUCED BY MAST CELLS, MACROPHAGES, ENDOTHELIAL CELLS, AND MANY OTHER CELL TYPES, AND ARE INVOLVED IN THE VASCULAR AND SYSTEMIC REACTIONS OF INFLAMMATION. THEY ARE GENERATED BY THE ACTIONS OF TWO CYCLOOXYGENASES CALLED COX-1 AND COX-2 LEUKOTRIENES ARE PRODUCED IN LEUKOCYTES AND MAST CELLS BY THE ACTION OF LIPOXYGENASE AND ARE INVOLVED IN VASCULAR AND SMOOTH MUSCLE REACTIONS AND LEUKOCYTE RECRUITMENT. CYTOKINES AND CHEMOKINES CYTOKINES ARE PROTEINS SECRETED BY MANY CELL TYPES (PRINCIPALLY ACTIVATED LYMPHOCYTES, MACROPHAGES, AND DENDRITIC CELLS, BUT ALSO ENDOTHELIAL, EPITHELIAL, AND CONNECTIVE TISSUE CELLS) THAT MEDIATE AND REGULATE IMMUNE AND INFLAMMATORY REACTIONS. CHEMOKINES ARE A FAMILY OF SMALL (8–10 KD) PROTEINS THAT ACT PRIMARILY AS CHEMOATTRACTANTS FOR SPECIFIC TYPES OF LEUKOCYTES. CHEMOKINES ARE CLASSIFIED INTO FOUR MAJOR GROUPS, ACCORDING TO THE ARRANGEMENT OF CYSTEINE (C) RESIDUES IN THE PROTEINS: C-X-C CHEMOKINES C-C CHEMOKINES C CHEMOKINES CX3C CHEMOKINES COMPLEMENT SYSTEM THE COMPLEMENT SYSTEM IS A COLLECTION OF SOLUBLE PROTEINS AND THEIR MEMBRANE RECEPTORS THAT FUNCTION MAINLY IN HOST DEFENSE AGAINST MICROBES AND IN PATHOLOGIC INFLAMMATORY REACTIONS. THE COMPLEMENT SYSTEM HAS THREE MAIN FUNCTIONS: INFLAMMATION. OPSONIZATION AND PHAGOCYTOSIS. CELL LYSIS.  MORPHOLOGIC PATTERN OF ACUTE INFLAMMATION THE MORPHOLOGIC HALLMARKS OF ACUTE INFLAMMATORY RESPONSES ARE CAUSED BY VASCULAR AND CELLULAR REACTIONS INCREASE BLOOD FLOW TO THE INJURED AREA AND INCREASED VASCULAR PERMEABILITY LEAD TO THE ACCUMULATION OF EXTRAVASCULAR FLUID RICH IN PLASMA PROTEINS (EDEMA) ACCOUNT FOR THE REDNESS (RUBOR), WARMTH (CALOR), AND SWELLING (TUMOR) LEUKOCYTES THAT ARE RECRUITED AND ACTIVATED CAUSING TISSUE DAMAGE AND LOSS OF FUNCTION (FUNCTIO LAESA). THE LIBERATION OF PROSTAGLANDINS, NEUROPEPTIDES, AND CYTOKINES, ONE OF THE LOCAL SYMPTOMS IS PAIN (DOLOR).  SPECIAL MORPHOLOGIC PATTERNS ARE OFTEN SUPERIMPOSED ON THEM, DEPENDING ON THE SEVERITY OF THE REACTION, ITS SPECIFIC CAUSE, AND THE PARTICULAR TISSUE AND SITE INVOLVED. SPECIAL MORPHOLOGIC PATTERNS ARE: SEROUS INFLAMMATION FIBRINOUS INFLAMMATION PURULENT (SUPPURATIVE) INFLAMMATION, ABSCESS ULCERS SEROUS INFLAMMATION THE EXUDATION OF CELL-POOR FLUID INTO SPACES CREATED BY INJURY TO SURFACE EPITHELIA OR INTO BODY CAVITIES LINED BY THE PERITONEUM, PLEURA, OR PERICARDIUM. TYPICALLY, THE FLUID IN SEROUS INFLAMMATION IS: NOT INFECTED BY DESTRUCTIVE ORGANISMS DOES NOT CONTAIN LARGE NUMBERS OF LEUKOCYTES IN BODY CAVITIES THE FLUID MAY BE DERIVED FROM THE PLASMA OR FROM THE SECRETIONS OF MESOTHELIAL CELLS (AS A RESULT OF LOCAL IRRITATION) → EFFUSION. THE SKIN BLISTER RESULTING FROM A BURN OR VIRAL INFECTION REPRESENTS ACCUMULATION OF SEROUS FLUID WITHIN OR IMMEDIATELY BENEATH THE DAMAGED EPIDERMIS OF THE SKIN FIBRINOUS INFLAMMATION A FIBRINOUS EXUDATE DEVELOPS WHEN THE VASCULAR LEAKS ARE LARGE OR THERE IS A LOCAL PROCOAGULANT STIMULUS A LARGE INCREASE IN VASCULAR PERMEABILITY, HIGHER-MOLECULAR WEIGHT PROTEINS SUCH AS FIBRINOGEN PASS OUT OF THE BLOOD, AND FIBRIN IS FORMED AND DEPOSITED IN THE EXTRACELLULAR SPACE, SUCH AS THE MENINGES, PERICARDIUM AND PLEURA. HISTOLOGICALLY, FIBRIN APPEARS AS AN EOSINOPHILIC MESHWORK OF THREADS OR SOMETIMES AS AN AMORPHOUS COAGULUM OR SOMETIMES AS AN AMORPHOUS COAGULUM FIBRINOUS EXUDATES MAY BE DISSOLVED BY FIBRINOLYSIS AND CLEARED BY MACROPHAGES. IF THE FIBRIN IS NOT REMOVED, WITH TIME, IT MAY STIMULATE THE INGROWTH OF FIBROBLASTS AND BLOOD VESSELS AND THUS LEAD TO SCARRING PURULENT (SUPPURATIVE) INFLAMMATION PURULENT INFLAMMATION IS CHARACTERIZED BY THE PRODUCTION OF PUS AN EXUDATE CONSISTING OF NEUTROPHILS, THE LIQUEFIED DEBRIS OF NECROTIC CELLS, AND EDEMA FLUID. THE MOST FREQUENT CAUSE OF PURULENT INFLAMMATION IS INFECTION WITH BACTERIA THAT CAUSE LIQUEFACTIVE TISSUE NECROSIS → STAPHYLOCOCCI A COMMON EXAMPLE: ACUTE APPENDICITIS ABSCESSES ARE LOCALIZED COLLECTIONS OF PUS CAUSED BY SUPPURATION BURIED IN A TISSUE, AN ORGAN, OR A CONFINED SPACE. THEY ARE PRODUCED BY SEEDING OF PYOGENIC BACTERIA INTO A TISSUE HISTOLOGY OF ABSCESS: ABSCESSES HAVE A CENTRAL REGION THAT APPEARS AS A MASS OF NECROTIC LEUKOCYTES AND TISSUE CELLS. THE OUTSIDE THIS REGION THERE MAY BE VASCULAR DILATION AND PARENCHYMAL AND FIBROBLASTIC PROLIFERATION WHEN PERSISTENT OR AT CRITICAL LOCATIONS (SUCH AS THE BRAIN), ABSCESSES MAY HAVE TO BE DRAINED SURGICALLY. ULCER AN ULCER IS A LOCAL DEFECT, OR EXCAVATION, OF THE SURFACE OF AN ORGAN OR TISSUE THAT IS PRODUCED BY THE SLOUGHING (SHEDDING) OF INFLAMED NECROTIC TISSUE. ULCERATION CAN OCCUR ONLY WHEN TISSUE NECROSIS AND RESULTANT INFLAMMATION EXIST ON OR NEAR A SURFACE. IT IS MOST COMMONLY ENCOUNTERED: THE MUCOSA OF THE MOUTH, STOMACH, INTESTINES, OR GENITOURINARY TRACT THE SKIN AND SUBCUTANEOUS TISSUE OF THE LOWER EXTREMITIES IN PERSONS WHO HAVE CIRCULATORY DISTURBANCES ACUTE AND CHRONIC INFLAMMATION OFTEN COEXIST IN ULCERS DURING THE ACUTE STAGE THERE IS INTENSE POLYMORPHONUCLEAR INFILTRATION AND VASCULAR DILATION IN THE MARGINS OF THE DEFECT. WITH CHRONICITY, THE MARGINS AND BASE OF THE ULCER DEVELOP FIBROBLAST PROLIFERATION, SCARRING, AND THE ACCUMULATION OF LYMPHOCYTES, MACROPHAGES, AND PLASMA CELLS.  OUTCOMES OF ACUTE INFLAMMATION COMPLETE RESOLUTION THE USUAL OUTCOME WHEN THE INJURY IS LIMITED OR SHORT-LIVED OR WHEN THERE HAS BEEN LITTLE TISSUE DESTRUCTION AND THE DAMAGED PARENCHYMAL CELLS CAN REGENERATE HEALING BY CONNECTIVE TISSUE REPLACEMENT (SCARRING, OR FIBROSIS). THIS OCCURS AFTER SUBSTANTIAL TISSUE DESTRUCTION, WHEN THE INFLAMMATORY INJURY INVOLVES TISSUES THAT ARE INCAPABLE OF REGENERATION, OR WHEN THERE IS ABUNDANT FIBRIN EXUDATION IN TISSUE OR IN SEROUS CAVITIES (PLEURA, PERITONEUM) THAT CANNOT BE ADEQUATELY CLEARED → FIBROUS TISSUE. PROGRESSION OF THE RESPONSE TO CHRONIC INFLAMMATION. ACUTE TO CHRONIC TRANSITION OCCURS WHEN THE ACUTE INFLAMMATORY RESPONSE CANNOT BE RESOLVED, AS A RESULT OF EITHER THE PERSISTENCE OF THE INJURIOUS AGENT OR SOME INTERFERENCE WITH THE NORMAL PROCESS OF HEALING.  CHRONIC INFLAMMATION CHRONIC INFLAMMATION IS A RESPONSE OF PROLONGED DURATION (WEEKS OR MONTHS) IN WHICH INFLAMMATION, TISSUE INJURY, AND ATTEMPTS AT REPAIR COEXIST, IN VARYING COMBINATIONS. IT MAY FOLLOW ACUTE INFLAMMATION, OR MAY BEGIN INSIDIOUSLY, AS A SMOLDERING, SOMETIMES PROGRESSIVE, PROCESS WITHOUT ANY SIGNS OF A PRECEDING ACUTE REACTION.  CAUSES OF CHRONIC INFLAMMATION PERSISTENT INFECTIONS HYPERSENSITIVITY DISEASES PROLONGED EXPOSURE TO POTENTIALLY TOXIC AGENTS, EITHER EXOGENOUS OR ENDOGENOUS INFLAMMATORY DISORDER PERSISTENT INFECTIONS CAUSED BY MICROORGANISMS THAT ARE DIFFICULT TO ERADICATE, SUCH AS MYCOBACTERIA AND CERTAIN VIRUSES, FUNGI, AND PARASITES. THESE ORGANISMS OFTEN EVOKE AN IMMUNE REACTION → DELAYED-TYPE HYPERSENSITIVITY. THE INFLAMMATORY RESPONSE SOMETIMES TAKES A SPECIFIC PATTERN → GRANULOMATOUS INFLAMMATION. IN OTHER CASES, UNRESOLVED ACUTE INFLAMMATION EVOLVES INTO CHRONIC INFLAMMATION, SUCH AS WHEN AN ACUTE BACTERIAL INFECTION OF THE LUNG PROGRESSES TO A CHRONIC LUNG ABSCESS. HYPERSENSITIVITY DISEASES. DISEASES THAT ARE CAUSED BY EXCESSIVE AND INAPPROPRIATE ACTIVATION OF THE IMMUNE SYSTEM. IN AUTOIMMUNE DISEASES, SELF (AUTO) ANTIGENS EVOKE A SELF-PERPETUATING IMMUNE REACTION THAT RESULTS IN CHRONIC INFLAMMATION AND TISSUE DAMAGE; EXAMPLES OF SUCH DISEASES ARE RHEUMATOID ARTHRITIS IN ALLERGIC DISEASES, CHRONIC INFLAMMATION IS THE RESULT OF EXCESSIVE IMMUNE RESPONSES AGAINST COMMON ENVIRONMENTAL SUBSTANCES, AS IN BRONCHIAL ASTHMA.  PROLONGED EXPOSURE TO POTENTIALLY TOXIC AGENTS, EITHER EXOGENOUS OR ENDOGENOUS. AN EXAMPLE OF AN EXOGENOUS AGENT IS PARTICULATE SILICA, A NON DEGRADABLE INANIMATE MATERIAL THAT, WHEN INHALED FOR PROLONGED PERIODS, RESULTS IN AN INFLAMMATORY LUNG DISEASE → SILICOSIS ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY PROCESS AFFECTING THE ARTERIAL WALL THAT IS THOUGHT TO BE INDUCED BY EXCESSIVE PRODUCTION AND TISSUE DEPOSITION OF ENDOGENOUS CHOLESTEROL AND OTHER LIPIDS. INFLAMMATORY DISORDER SOME FORMS OF CHRONIC INFLAMMATION MAY BE IMPORTANT IN THE PATHOGENESIS OF DISEASES THAT ARE NOT CONVENTIONALLY THOUGHT OF AS INFLAMMATORY DISORDERS. THESE INCLUDE NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER DISEASE AND CERTAIN CANCERS IN WHICH INFLAMMATORY REACTIONS PROMOTE TUMOR DEVELOPMENT.  MORPHOLOGIC FEATURES OF CHRONIC INFLAMMATION INFILTRATION WITH MONONUCLEAR CELLS, WHICH INCLUDE MACROPHAGES, LYMPHOCYTES, AND PLASMA CELLS TISSUE DESTRUCTION, INDUCED BY THE PERSISTENT OFFENDING AGENT OR BY THE INFLAMMATORY CELLS ATTEMPTS AT HEALING BY CONNECTIVE TISSUE REPLACEMENT OF DAMAGED TISSUE, ACCOMPLISHED BY ANGIOGENESIS (PROLIFERATION OF SMALL BLOOD VESSELS) AND, IN PARTICULAR, FIBROSIS  CELLS AND MEDIATORS OF CHRONIC INFLAMMATION MACROPHAGES LYMPHOCYTE OTHER CELLS IN CHRONIC INFLAMMATION THE ROLE OF MACROPHAGES MACROPHAGES ARE THE DOMINANT CELLS IN MOST CHRONIC INFLAMMATORY REACTIONS. MACROPHAGES CONTRIBUTE TO THE REACTION BY SECRETING CYTOKINES AND GROWTH FACTORS THAT ACT ON VARIOUS CELLS, BY DESTROYING FOREIGN INVADERS AND TISSUES, AND BY ACTIVATING OTHER CELLS, NOTABLY T LYMPHOCYTES.  MACROPHAGES ARE TISSUE CELLS DERIVED FROM HEMATOPOIETIC STEM CELLS IN THE BONE MARROW AND FROM PROGENITORS IN THE EMBRYONIC YOLK SAC AND FETAL LIVER DURING EARLY DEVELOPMENT. CIRCULATING CELLS OF THIS LINEAGE ARE KNOWN AS MONOCYTES. MACROPHAGES ARE NORMALLY DIFFUSELY SCATTERED IN MOST CONNECTIVE TISSUES. IN ADDITION, THEY ARE FOUND IN SPECIFIC LOCATIONS IN ORGANS SUCH AS THE LIVER (KUPFFER CELLS), SPLEEN AND LYMPH NODES (SINUS HISTIOCYTES), CENTRAL NERVOUS SYSTEM (MICROGLIAL CELLS), AND LUNGS (ALVEOLAR MACROPHAGES). TOGETHER THESE CELLS COMPRISE THE MONONUCLEAR PHAGOCYTE SYSTEM, ALSO KNOWN BY THE OLDER (AND INACCURATE) NAME OF RETICULOENDOTHELIAL SYSTEM.  IN INFLAMMATORY REACTIONS, PROGENITORS IN THE BONE MARROW GIVE RISE TO MONOCYTES, WHICH ENTER THE BLOOD, MIGRATE INTO VARIOUS TISSUES, AND DIFFERENTIATE INTO MACROPHAGES. ENTRY OF BLOOD MONOCYTES INTO TISSUES IS GOVERNED BY THE SAME FACTORS THAT ARE INVOLVED IN NEUTROPHIL EMIGRATION, SUCH AS ADHESION MOLECULES AND CHEMOKINES. THE HALF-LIFE OF BLOOD MONOCYTES IS ABOUT 1 DAY, WHEREAS THE LIFE SPAN OF TISSUE MACROPHAGES IS SEVERAL MONTHS OR YEARS. THUS, MACROPHAGES OFTEN BECOME THE DOMINANT CELL POPULATION IN INFLAMMATORY REACTIONS WITHIN 48 HOURS OF ONSET. THE MACROPHAGES THAT RESIDE IN TISSUES IN THE STEADY STATE (IN THE ABSENCE OF TISSUE INJURY OR INFLAMMATION), SUCH AS MICROGLIA, KUPFFER CELLS, AND ALVEOLAR MACROPHAGES, ARISE FROM THE YOLK SAC OR FETAL LIVER VERY EARLY IN EMBRYOGENESIS, POPULATE THE TISSUES, STAY FOR LONG PERIODS, AND ARE REPLENISHED MAINLY BY THE PROLIFERATION OF RESIDENT CELLS. THERE ARE TWO MAJOR PATHWAYS OF MACROPHAGE ACTIVATION: CLASSICAL MACROPHAGE ACTIVATION ALTERNATIVE MACROPHAGE ACTIVATION CLASSICAL MACROPHAGE ACTIVATION THIS ACTIVATION MAY BE INDUCED BY: MICROBIAL PRODUCTS SUCH AS ENDOTOXIN, WHICH ENGAGE TLR AND OTHER SENSORS. T CELL–DERIVED SIGNALS, IMPORTANTLY THE CYTOKINE IFN-Γ, IN IMMUNE RESPONSES. CLASSICALLY ACTIVATED (ALSO CALLED M1) MACROPHAGES PRODUCE NO AND ROS UPREGULATE LYSOSOMAL ENZYMES ALL OF WHICH ENHANCE THEIR ABILITY TO KILL INGESTED ORGANISMS SECRETE CYTOKINES THAT STIMULATE INFLAMMATION THESE MACROPHAGES ARE IMPORTANT IN HOST DEFENSE AGAINST MICROBES AND IN MANY INFLAMMATORY REACTIONS ALTERNATIVE MACROPHAGE ACTIVATION THIS ACTIVATION IS INDUCED BY: CYTOKINES OTHER THAN IFN-Γ, SUCH AS IL-4 AND IL-13, PRODUCED BY T LYMPHOCYTES AND OTHER CELLS. THESE MACROPHAGES ARE NOT ACTIVELY MICROBICIDAL; INSTEAD, THE PRINCIPAL FUNCTION OF ALTERNATIVELY ACTIVATED (M2) MACROPHAGES IS IN TISSUE REPAIR. THEY SECRETE GROWTH FACTORS THAT PROMOTE ANGIOGENESIS, ACTIVATE FIBROBLASTS, AND STIMULATE COLLAGEN SYNTHESIS. ROLE OF LYMPHOCYTES MICROBES AND OTHER ENVIRONMENTAL ANTIGENS ACTIVATE T AND B LYMPHOCYTES, WHICH AMPLIFY AND PROPAGATE CHRONIC INFLAMMATION. ALTHOUGH THE MAJOR FUNCTION OF THESE LYMPHOCYTES IS AS THE MEDIATORS OF ADAPTIVE IMMUNITY, WHICH PROVIDES DEFENSE AGAINST INFECTIOUS PATHOGENS, THESE CELLS ARE OFTEN PRESENT IN CHRONIC INFLAMMATION AND, WHEN THEY ARE ACTIVATED, THE INFLAMMATION TENDS TO BE PERSISTENT AND SEVERE. SOME OF THE STRONGEST CHRONIC INFLAMMATORY REACTIONS, SUCH AS GRANULOMATOUS INFLAMMATION, ARE DEPENDENT ON LYMPHOCYTE RESPONSES. LYMPHOCYTES MAY BE THE DOMINANT POPULATION IN THE CHRONIC INFLAMMATION SEEN IN AUTOIMMUNE AND OTHER HYPERSENSITIVITY DISEASES.  BY VIRTUE OF THEIR ABILITY TO SECRETE CYTOKINES, CD4+ T LYMPHOCYTES PROMOTE INFLAMMATION AND INFLUENCE THE NATURE OF THE INFLAMMATORY REACTION. THERE ARE THREE SUBSETS OF CD4+ T CELLS THAT SECRETE DIFFERENT CYTOKINES AND ELICIT DIFFERENT TYPES OF INFLAMMATION. TH1 CELLS PRODUCE THE CYTOKINE IFN-Γ, WHICH ACTIVATES MACROPHAGES BY THE CLASSICAL PATHWAY. TH2 CELLS SECRETE IL-4, IL-5, AND IL-13, WHICH RECRUIT AND ACTIVATE EOSINOPHILS AND ARE RESPONSIBLE FOR THE ALTERNATIVE PATHWAY OF MACROPHAGE ACTIVATION. TH17 CELLS SECRETE IL-17 AND OTHER CYTOKINES, WHICH INDUCE THE SECRETION OF CHEMOKINES RESPONSIBLE FOR RECRUITING NEUTROPHILS INTO THE REACTION BOTH TH1 AND TH17 CELLS ARE INVOLVED IN DEFENSE AGAINST MANY TYPES OF BACTERIA AND VIRUSES AND IN AUTOIMMUNE DISEASES. TH2 CELLS ARE IMPORTANT IN DEFENSE AGAINST HELMINTHIC PARASITES AND IN ALLERGIC INFLAMMATION. LYMPHOCYTES AND MACROPHAGES INTERACT IN A BIDIRECTIONAL WAY, AND THESE INTERACTIONS PLAY AN IMPORTANT ROLE IN PROPAGATING CHRONIC INFLAMMATION. MACROPHAGES DISPLAY ANTIGENS TO T CELLS → EXPRESS MEMBRANE MOLECULES (CALLED COSTIMULATORS) THAT ACTIVATE T CELLS. PRODUCE CYTOKINES (IL-12 AND OTHERS) THAT ALSO STIMULATE T CELL RESPONSES. ACTIVATED T LYMPHOCYTES, IN TURN, PRODUCE CYTOKINES → WHICH RECRUIT AND ACTIVATE MACROPHAGES, PROMOTING MORE ANTIGEN PRESENTATION AND CYTOKINE SECRETION. THE RESULT IS A CYCLE OF CELLULAR REACTIONS THAT FUEL AND SUSTAIN CHRONIC INFLAMMATION.  ACTIVATED B LYMPHOCYTES AND ANTIBODY-PRODUCING PLASMA CELLS ARE OFTEN PRESENT AT SITES OF CHRONIC INFLAMMATION. THE ANTIBODIES MAY BE SPECIFIC FOR PERSISTENT FOREIGN OR SELF ANTIGENS IN THE INFLAMMATORY SITE OR AGAINST ALTERED TISSUE COMPONENTS. HOWEVER, THE SPECIFICITY AND EVEN THE IMPORTANCE OF ANTIBODIES IN MOST CHRONIC INFLAMMATORY DISORDERS ARE UNCLEAR.  IN SOME CHRONIC INFLAMMATORY REACTIONS, THE ACCUMULATED LYMPHOCYTES, ANTIGEN- PRESENTING CELLS, AND PLASMA CELLS CLUSTER TOGETHER TO FORM LYMPHOID STRUCTURES RESEMBLING THE FOLLICLES FOUND IN LYMPH NODES → TERTIARY LYMPHOID ORGANS THIS TYPE OF LYMPHOID ORGANOGENESIS IS OFTEN SEEN IN: THE SYNOVIUM OF PATIENTS WITH LONGSTANDING RHEUMATOID ARTHRITIS THE THYROID IN HASHIMOTO THYROIDITIS THE GASTRIC MUCOSA IN THE SETTING OF HELICOBACTER PYLORI INFECTION. OTHER CELLS IN CHRONIC INFLAMMATION EOSINOPHIL EOSINOPHILS ARE ABUNDANT IN IMMUNE REACTIONS MEDIATED BY IG-E AND IN PARASITIC INFECTIONS. THEIR RECRUITMENT IS DRIVEN BY ADHESION MOLECULES SIMILAR TO THOSE USED BY NEUTROPHILS, AND BY SPECIFIC CHEMOKINES (E.G., EOTAXIN) DERIVED FROM LEUKOCYTES AND EPITHELIAL CELLS. EOSINOPHILS HAVE GRANULES THAT CONTAIN MAJOR BASIC PROTEIN, A HIGHLY CATIONIC PROTEIN THAT IS TOXIC TO PARASITES BUT ALSO INJURES HOST EPITHELIAL CELLS. THIS IS WHY EOSINOPHILS ARE OF BENEFIT IN CONTROLLING PARASITIC INFECTIONS, YET ALSO CONTRIBUTE TO TISSUE DAMAGE IN IMMUNE REACTIONS SUCH AS ALLERGIES. MAST CELLS MAST CELLS ARE WIDELY DISTRIBUTED IN CONNECTIVE TISSUES AND PARTICIPATE IN BOTH ACUTE AND CHRONIC INFLAMMATORY REACTIONS. MAST CELLS EXPRESS RECEPTOR ON THEIR SURFACE, WHICH BINDS IG-E ANTIBODY. IN IMMEDIATE HYPERSENSITIVITY REACTIONS, IG-E BOUND TO THE MAST CELLS’ RECEPTORS SPECIFICALLY RECOGNIZES ANTIGEN, AND IN RESPONSE THE CELLS DEGRANULATE AND RELEASE MEDIATORS, SUCH AS HISTAMINE AND PROSTAGLANDINS. THIS TYPE OF RESPONSE OCCURS DURING ALLERGIC REACTIONS TO FOODS, INSECT VENOM, OR DRUGS, SOMETIMES WITH CATASTROPHIC RESULTS (E.G., ANAPHYLACTIC SHOCK). MAST CELLS ALSO ARE PRESENT IN CHRONIC INFLAMMATORY REACTIONS, AND BECAUSE THEY SECRETE A PLETHORA OF CYTOKINES, THEY CAN PROMOTE INFLAMMATORY REACTIONS. NEUTROPHILS ALTHOUGH NEUTROPHILS ARE CHARACTERISTIC OF ACUTE INFLAMMATION, MANY FORMS OF CHRONIC INFLAMMATION, LASTING FOR MONTHS, CONTINUE TO SHOW LARGE NUMBERS OF NEUTROPHILS, INDUCED EITHER BY PERSISTENT MICROBES OR BY CYTOKINES AND OTHER MEDIATORS PRODUCED BY ACTIVATED MACROPHAGES AND T LYMPHOCYTES. IN CHRONIC BACTERIAL INFECTION OF BONE (OSTEOMYELITIS), A NEUTROPHILIC EXUDATE CAN PERSIST FOR MANY MONTHS. NEUTROPHILS ALSO ARE IMPORTANT IN THE CHRONIC DAMAGE INDUCED IN LUNGS BY SMOKING AND OTHER IRRITANT STIMULI. THIS PATTERN OF INFLAMMATION HAS BEEN CALLED ACUTE ON CHRONIC INFLAMMATION. GRANULOMATOUS INFLAMMATION GRANULOMATOUS INFLAMMATION IS A FORM OF CHRONIC INFLAMMATION CHARACTERIZED BY COLLECTIONS OF ACTIVATED MACROPHAGES, OFTEN WITH T LYMPHOCYTES, AND SOMETIMES ASSOCIATED WITH CENTRAL NECROSIS. THE ACTIVATED MACROPHAGES MAY DEVELOP ABUNDANT CYTOPLASM AND BEGIN TO RESEMBLE EPITHELIAL CELLS, AND ARE CALLED EPITHELIOID CELLS. SOME ACTIVATED MACROPHAGES MAY FUSE, FORMING MULTINUCLEATE GIANT CELLS. GRANULOMA FORMATION IS A CELLULAR ATTEMPT TO CONTAIN AN OFFENDING AGENT THAT IS DIFFICULT TO ERADICATE. IN THIS ATTEMPT THERE IS OFTEN STRONG ACTIVATION OF T LYMPHOCYTES LEADING TO MACROPHAGE ACTIVATION, WHICH CAN CAUSE INJURY TO NORMAL TISSUES THERE ARE TWO TYPES OF GRANULOMAS, WHICH DIFFER IN THEIR PATHOGENESIS. IMMUNE GRANULOMAS A GRANULOMATOUS INFLAMMATION ARE CAUSED BY A VARIETY OF AGENTS THAT ARE CAPABLE OF INDUCING A PERSISTENT T CELL–MEDIATED IMMUNE RESPONSE. THIS TYPE OF IMMUNE RESPONSE PRODUCES GRANULOMAS USUALLY WHEN THE INCITING AGENT CANNOT BE READILY ELIMINATED, SUCH AS A PERSISTENT MICROBE OR A SELF ANTIGEN. IN SUCH RESPONSES, MACROPHAGES ACTIVATE T CELLS TO PRODUCE CYTOKINES, SUCH AS: IL-2, WHICH ACTIVATES OTHER T CELLS, PERPETUATING THE RESPONSE IFN-Γ, WHICH ACTIVATES THE MACROPHAGES. FOREIGN BODY GRANULOMAS A GRANULOMATOUS INFLAMMATION ARE SEEN IN RESPONSE TO RELATIVELY INERT FOREIGN BODIES, IN THE ABSENCE OF T CELL– MEDIATED IMMUNE RESPONSES. TYPICALLY, FOREIGN BODY GRANULOMAS FORM AROUND MATERIALS SUCH AS TALC, SUTURES, OR OTHER FIBERS THAT ARE LARGE ENOUGH TO PRECLUDE PHAGOCYTOSIS BY A MACROPHAGE BUT ARE NOT IMMUNOGENIC. MORPHOLOGY OF GRANULOMATOUS INFLAMMATION IN THE USUAL H&E STAINED TISSUE SAMPLES, THE ACTIVATED MACROPHAGES IN GRANULOMAS HAVE PINK GRANULAR CYTOPLASM WITH INDISTINCT CELL BOUNDARIES AND ARE CALLED EPITHELIOID CELLS. A COLLAR OF LYMPHOCYTES SURROUNDS THE AGGREGATES OF EPITHELIOID MACROPHAGES. OLDER GRANULOMAS MAY HAVE A RIM OF FIBROBLASTS AND CONNECTIVE TISSUE. FREQUENTLY, BUT NOT INVARIABLY, MULTINUCLEATED GIANT CELLS 40 TO 50 MILLI MICRONS IN DIAMETER → LANGHANS GIANT CELLS (A LARGE MASS OF CYTOPLASM AND MANY NUCLEI) GRANULOMAS ASSOCIATED WITH CERTAIN INFECTIOUS ORGANISMS (CLASSICALLY MYCOBACTERIUM TUBERCULOSIS) OFTEN CONTAIN A CENTRAL ZONE OF NECROSIS. GROSSLY, THIS HAS A GRANULAR, CHEESY APPEARANCE AND IS THEREFORE CALLED CASEOUS NECROSIS. MICROSCOPICALLY, THIS NECROTIC MATERIAL APPEARS AS AMORPHOUS, STRUCTURELESS, EOSINOPHILIC, GRANULAR DEBRIS, WITH LOSS OF CELLULAR DETAILS. THE GRANULOMAS IN CROHN DISEASE, SARCOIDOSIS, AND FOREIGN BODY REACTIONS TEND TO NOT HAVE NECROTIC CENTER AND ARE SAID TO BE NONCASEATING. HEALING OF GRANULOMAS IS ACCOMPANIED BY FIBROSIS THAT MAY BE EXTENSIVE.  SYSTEMIC EFFECTS OF INFLAMMATION INFLAMMATION, EVEN IF IT IS LOCALIZED, IS ASSOCIATED WITH CYTOKINE-INDUCED SYSTEMIC REACTIONS THAT ARE COLLECTIVELY CALLED THE ACUTE-PHASE RESPONSE. THE SYSTEMIC MANIFESTATIONS OF ACUTE INFLAMMATION ARE REACTIONS TO CYTOKINES WHOSE PRODUCTION IS STIMULATED BY BACTERIAL PRODUCTS SUCH AS LPS, VIRAL DOUBLE STRANDED RNA AND BY OTHER INFLAMMATORY STIMULI. THE CYTOKINES TNF, IL-1, AND IL-6 ARE IMPORTANT MEDIATORS OF THE ACUTE PHASE REACTION. THE ACUTE-PHASE RESPONSE CONSISTS OF SEVERAL CLINICAL AND PATHOLOGIC CHANGES: FEVER ACUTE-PHASE PROTEINS LEUKOCYTOSIS OTHER MANIFESTATIONS FEVER FEVER CHARACTERIZED BY AN ELEVATION OF BODY TEMPERATURE, USUALLY BY 1° TO 4°C. FEVER IS ONE OF THE MOST PROMINENT MANIFESTATIONS OF THE ACUTE-PHASE RESPONSE, ESPECIALLY WHEN INFLAMMATION IS ASSOCIATED WITH INFECTION. SUBSTANCES THAT INDUCE FEVER ARE CALLED PYROGENS.  THE INCREASE IN BODY TEMPERATURE IS CAUSED BY PROSTAGLANDINS THAT ARE PRODUCED IN THE VASCULAR AND PERIVASCULAR CELLS OF THE HYPOTHALAMUS. BACTERIAL PRODUCTS, SUCH AS LPS (CALLED EXOGENOUS PYROGENS), STIMULATE LEUKOCYTES TO RELEASE CYTOKINES SUCH AS IL-1 AND TNF (CALLED ENDOGENOUS PYROGENS) THAT INCREASE THE ENZYMES (CYCLOOXYGENASES) THAT CONVERT ARACHADONIC ACID INTO PROSTAGLANDINS. IN THE HYPOTHALAMUS, THE PROSTAGLANDINS, ESPECIALLY PGE2, STIMULATE THE PRODUCTION OF NEUROTRANSMITTERS THAT RESET THE TEMPERATURE SET POINT AT A HIGHER LEVEL. NSAIDS, INCLUDING ASPIRIN, REDUCE FEVER BY INHIBITING PROSTAGLANDIN SYNTHESIS. https://basicmedicalkey.com/signs-and-symptoms/ ACUTE-PHASE PROTEINS ACUTE-PHASE PROTEIN ARE PLASMA PROTEINS, MOSTLY SYNTHESIZED IN THE LIVER, WHOSE PLASMA CONCENTRATIONS MAY INCREASE SEVERAL HUNDRED-FOLD AS PART OF THE RESPONSE TO INFLAMMATORY STIMULI. THREE OF THE BEST-KNOWN: C-REACTIVE PROTEIN (CRP) FIBRINOGEN SERUM AMYLOID A (SAA) PROTEIN. SYNTHESIS OF THESE MOLECULES IN HEPATOCYTES IS STIMULATED BY CYTOKINES.  MANY ACUTE-PHASE PROTEINS, SUCH AS CRP AND SAA, BIND TO MICROBIAL CELL WALLS, AND THEY MAY ACT AS OPSONINS. FIBRINOGEN BINDS TO RED CELLS AND CAUSES THEM TO FORM STACKS (ROULEAUX) THAT SEDIMENT MORE RAPIDLY AT UNIT GRAVITY THAN DO INDIVIDUAL RED CELLS. THIS IS THE BASIS FOR MEASURING THE ERYTHROCYTE SEDIMENTATION RATE AS A SIMPLE TEST FOR AN INFLAMMATORY RESPONSE CAUSED BY ANY STIMULUS. http://www.medical-labs.net/autoagglutination-vs-rouleaux-formation-2605/ ACUTE-PHASE PROTEINS HAVE BENEFICIAL EFFECTS DURING ACUTE INFLAMMATION, BUT PROLONGED PRODUCTION OF THESE PROTEINS (ESPECIALLY SAA) IN STATES OF CHRONIC INFLAMMATION CAN CAUSE SECONDARY AMYLOIDOSIS.  ELEVATED SERUM LEVELS OF CRP SERVE AS A MARKER FOR INCREASED RISK OF MYOCARDIAL INFARCTION IN PATIENTS WITH CORONARY ARTERY DISEASE. IT IS POSTULATED THAT INFLAMMATION INVOLVING ATHEROSCLEROTIC PLAQUES IN THE CORONARY ARTERIES PREDISPOSES TO THROMBOSIS AND SUBSEQUENT INFARCTION. ANOTHER PEPTIDE WHOSE PRODUCTION IS INCREASED IN THE ACUTE-PHASE RESPONSE IS THE IRON-REGULATING PEPTIDE HEPCIDIN. CHRONICALLY ELEVATED PLASMA CONCENTRATIONS OF HEPCIDIN REDUCE THE AVAILABILITY OF IRON AND ARE RESPONSIBLE FOR THE ANEMIA ASSOCIATED WITH CHRONIC INFLAMMATION. LEUKOCYTOSIS IT IS A COMMON FEATURE OF INFLAMMATORY REACTIONS, ESPECIALLY THOSE INDUCED BY BACTERIAL INFECTIONS. THE LEUKOCYTE COUNT USUALLY CLIMBS TO 15,000 OR 20,000 CELLS/ML, BUT SOMETIMES IT MAY REACH EXTRAORDINARILY HIGH LEVELS OF 40,000 TO 100,000 CELLS/ML. THESE EXTREME ELEVATIONS ARE REFERRED TO AS LEUKEMOID REACTIONS  THE LEUKOCYTOSIS OCCURS INITIALLY BECAUSE OF: ACCELERATED RELEASE OF CELLS FROM THE BONE MARROW POSTMITOTIC RESERVE POOL (CAUSED BY CYTOKINES, INCLUDING TNF AND IL-1) ASSOCIATED WITH A RISE IN THE NUMBER OF MORE IMMATURE NEUTROPHILS IN THE BLOOD, REFERRED TO AS A SHIFT TO THE LEFT. MOST BACTERIAL INFECTIONS INDUCE AN INCREASE IN THE BLOOD NEUTROPHIL COUNT, CALLED NEUTROPHILIA VIRAL INFECTIONS, SUCH AS INFECTIOUS MONONUCLEOSIS, MUMPS, AND GERMAN MEASLES, CAUSE AN ABSOLUTE INCREASE IN THE NUMBER OF LYMPHOCYTES (LYMPHOCYTOSIS) IN SOME ALLERGIES AND PARASITIC INFESTATIONS, THERE IS AN INCREASE IN THE NUMBER OF BLOOD EOSINOPHILS, CREATING AN EOSINOPHILIA. CERTAIN INFECTIONS (TYPHOID FEVER AND INFECTIONS CAUSED BY SOME VIRUSES, RICKETTSIAE, AND CERTAIN PROTOZOA) ARE ASSOCIATED WITH A DECREASED NUMBER OF CIRCULATING WHITE CELLS (LEUKOPENIA)  OTHER MANIFESTATION INCREASED HEART RATE AND BLOOD PRESSURE; DECREASED SWEATING, MAINLY BECAUSE OF REDIRECTION OF BLOOD FLOW FROM CUTANEOUS TO DEEP VASCULAR BEDS, TO MINIMIZE HEAT LOSS THROUGH THE SKIN; RIGORS (SHIVERING), CHILLS (SEARCH FOR WARMTH), ANOREXIA, SOMNOLENCE, AND MALAISE, PROBABLY BECAUSE OF THE ACTIONS OF CYTOKINES ON BRAIN CELLS. THANK YOU