An An ulcerulcer : :- Is a local defect, or excavation, of the surface of an organ or tissue that is - Is a local defect, or excavation, of the surface of an organ or tissue that is

produced by necrosis of cells and sloughing (shedding) of necrotic and produced by necrosis of cells and sloughing (shedding) of necrotic and inflammatory tissue inflammatory tissue

- Ulceration can occur only when tissue necrosis and resultant inflammation - Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. Ulcers are most commonly encountered in exist on or near a surface. Ulcers are most commonly encountered in

1. mucosa of the mouth, stomach, intestines, or genitourinary tract1. mucosa of the mouth, stomach, intestines, or genitourinary tract 2. in the subcutaneous tissues of the lower extremities in older persons who 2. in the subcutaneous tissues of the lower extremities in older persons who

have circulatory disturbances predisposing affected tissue to extensive have circulatory disturbances predisposing affected tissue to extensive necrosisnecrosis

- Ulcerations are best exemplified by peptic ulcer of the stomach or - Ulcerations are best exemplified by peptic ulcer of the stomach or duodenum, in which acute and chronic inflammation coexist. duodenum, in which acute and chronic inflammation coexist.

- - During the acute stage, there is intense polymorphonuclear infiltration and During the acute stage, there is intense polymorphonuclear infiltration and vascular dilation in the margins of the defect. vascular dilation in the margins of the defect.

- With chronicity, the margins and base of the ulcer develop scarring with - With chronicity, the margins and base of the ulcer develop scarring with accumulation of lymphocytes, macrophages, and plasma cells.accumulation of lymphocytes, macrophages, and plasma cells.

Duodenal ulcerDuodenal ulcer

• Chemical Mediators of inflammationChemical Mediators of inflammation11. . Mediators may be produced:Mediators may be produced:a. Locally by cells at the site of inflammation, or a. Locally by cells at the site of inflammation, or b. Derived from circulating inactive precursors (typically synthesized b. Derived from circulating inactive precursors (typically synthesized

by the liver) that are activated at the site of inflammation by the liver) that are activated at the site of inflammation - Cell-derived mediators are normally sequestered in intracellular - Cell-derived mediators are normally sequestered in intracellular

granules and are rapidly secreted upon cellular activation (e.g., granules and are rapidly secreted upon cellular activation (e.g., histamine in mast cells) or are synthesized de novo in response to histamine in mast cells) or are synthesized de novo in response to a stimulus (e.g., prostaglandins produced by leukocytes) a stimulus (e.g., prostaglandins produced by leukocytes)

- Plasma protein-derived mediators (complement proteins, kinins) - Plasma protein-derived mediators (complement proteins, kinins) circulate in an inactive form and undergo proteolytic cleavage to circulate in an inactive form and undergo proteolytic cleavage to acquire their biologic activitiesacquire their biologic activities..

2. Most mediators act by binding to specific receptors on different 2. Most mediators act by binding to specific receptors on different target cellstarget cells

-. -. Such mediators may act on only one or a very few cell types, or Such mediators may act on only one or a very few cell types, or they may have diverse actions they may have diverse actions

- Other mediators (lysosomal proteases, ROS) have direct enzymatic - Other mediators (lysosomal proteases, ROS) have direct enzymatic activities that do not require binding to specific receptors.activities that do not require binding to specific receptors.

3. The actions of most mediators are tightly regulated and short-lived 3. The actions of most mediators are tightly regulated and short-lived and oand once activated and released from the cell,nce activated and released from the cell,

a. Some mediators quickly decay (e.g., arachidonic acid metabolites)a. Some mediators quickly decay (e.g., arachidonic acid metabolites) b. Some inactivated by enzymes ( kininase inactivates bradykinin)b. Some inactivated by enzymes ( kininase inactivates bradykinin)c. Some eliminated (antioxidants scavenge toxic oxygen metabolites)c. Some eliminated (antioxidants scavenge toxic oxygen metabolites)d. Or are inhibited (e.g.,Complement regulatory proteins)d. Or are inhibited (e.g.,Complement regulatory proteins) I. Cell-Derived MediatorsI. Cell-Derived Mediators- Produced by tissue macrophages, mast cells, and endothelial - Produced by tissue macrophages, mast cells, and endothelial

cells along with recruited leukocytes cells along with recruited leukocytes 1. Vasoactive Amines 1. Vasoactive Amines : histamine and serotonin: histamine and serotonin- Are among the first mediators to be released in acute inflammation- Are among the first mediators to be released in acute inflammation

Histamine: PHistamine: Produced mainly by mast cells ,basophils and plateletsroduced mainly by mast cells ,basophils and platelets- Is released from mast cell granules in response to:- Is released from mast cell granules in response to:1. Physical injury such as trauma or heat;1. Physical injury such as trauma or heat;2. Immune reactions involving binding of IgE antibodies to Fc receptors on mast 2. Immune reactions involving binding of IgE antibodies to Fc receptors on mast

cells( in bronchial asthma)cells( in bronchial asthma)3. C3a and C5a fragments of complement, the so-called anaphylatoxins 3. C3a and C5a fragments of complement, the so-called anaphylatoxins 4. Neuropeptides (e.g., substance P) 4. Neuropeptides (e.g., substance P) 5. Cytokines like IL-1 and IL-85. Cytokines like IL-1 and IL-8 - In humans, histamine causes :- In humans, histamine causes :a. Arteriolar dilation anda. Arteriolar dilation andb. Rapidly increases vascular permeability b. Rapidly increases vascular permeability - Histamine is inactivated by histaminase- Histamine is inactivated by histaminase

2. Arachidonic Acid Metabolites (AA):2. Arachidonic Acid Metabolites (AA):- The AA metabolites are involved in inflammation.- The AA metabolites are involved in inflammation. - AA metabolites, also called - AA metabolites, also called eicosanoidseicosanoids (because they are derived (because they are derived

from 20-carbon fatty acids-Greek from 20-carbon fatty acids-Greek eicosaeicosa, "twenty, "twenty- Their synthesis is increased at sites of inflammatory response, and - Their synthesis is increased at sites of inflammatory response, and

agents that inhibit their synthesis also diminish inflammationagents that inhibit their synthesis also diminish inflammation- Are produced by Leukocytes, mast cells, and platelets- Are produced by Leukocytes, mast cells, and platelets- AA-derived mediators act locally at the site of generation and then - AA-derived mediators act locally at the site of generation and then

decay spontaneously or are enzymatically destroyed decay spontaneously or are enzymatically destroyed - AA is a 20-carbon polyunsaturated fatty acid produced primarily from - AA is a 20-carbon polyunsaturated fatty acid produced primarily from

dietary linoleic acid and present in the body mainly in its esterified form dietary linoleic acid and present in the body mainly in its esterified form as a component of cell membrane phospholipids as a component of cell membrane phospholipids

- It is released from these phospholipids through the action of - It is released from these phospholipids through the action of phospholipases that have been activated by mechanical, phospholipases that have been activated by mechanical,

chemical, physical stimuli, or mediators such as C5achemical, physical stimuli, or mediators such as C5a - AA metabolism proceeds along one of two major pathways : - AA metabolism proceeds along one of two major pathways : A. Cyclooxygenase stimulates the synthesis of prostaglandins-A. Cyclooxygenase stimulates the synthesis of prostaglandins- and thromboxanesand thromboxanesB. Lipoxygenase is responsible for production of leukotrienes and B. Lipoxygenase is responsible for production of leukotrienes and

lipoxinslipoxinsA. Prostaglandins and thromboxanesA. Prostaglandins and thromboxanes- Products of the cyclooxygenase pathway include :. - Products of the cyclooxygenase pathway include :. 1. Prostaglandins E1. Prostaglandins E22 (PGE (PGE22), PGD), PGD22, PGF, PGF2α2α, PGI, PGI22

2. And thromboxane A2. And thromboxane A22 (TXA (TXA22), ),

- Each derived by the action of a specific enzyme on an - Each derived by the action of a specific enzyme on an ntermediate .and some of these enzymes have a restricted tissue ntermediate .and some of these enzymes have a restricted tissue distributiondistribution

a. a. PlateletsPlatelets contain the enzyme contain the enzyme thromboxane synthase,thromboxane synthase, and hence and hence TXATXA22 , which is a potent platelet-aggregating agent and , which is a potent platelet-aggregating agent and vasoconstrictor vasoconstrictor

b. b. Endothelial cellsEndothelial cells, lack thromboxane synthase but contain , lack thromboxane synthase but contain prostacyclin synthase, responsible for the formation of prostacyclin synthase, responsible for the formation of PGIPGI22,which ,which is a vasodilator and a potent inhibitor of platelet aggregation.is a vasodilator and a potent inhibitor of platelet aggregation.

c. c. Mast cells:Mast cells: PGD PGD22 is the major metabolite of the cyclooxygenase is the major metabolite of the cyclooxygenase pathway in mast cells; and along with PGEpathway in mast cells; and along with PGE22 and PGF2 it causes and PGF2 it causes vasodilatoion and potentiates edema formationvasodilatoion and potentiates edema formation

NoteNote PGE2 contributes to the pain and fever in acute inflammation PGE2 contributes to the pain and fever in acute inflammation B. Leukotrienes:B. Leukotrienes:- Are produced by the action of 5-lipoxygenase, the major AA-- Are produced by the action of 5-lipoxygenase, the major AA-

metabolizing enzyme in neutrophils and their synthesis involves metabolizing enzyme in neutrophils and their synthesis involves multiple stepsmultiple steps

- The first step generates leukotriene A- The first step generates leukotriene A44 (LTA (LTA44), which in turn gives ), which in turn gives rise to LTBrise to LTB44 or LTC or LTC44

1. LTB1. LTB44 is produced by neutrophils and is a potent chemotactic is produced by neutrophils and is a potent chemotactic agent for neutrophilsagent for neutrophils

2. LTC2. LTC44 and its subsequent metabolites, LTD and its subsequent metabolites, LTD44 and LTE and LTE44, are , are produced mainly in mast cells and cause bronchoconstrictionproduced mainly in mast cells and cause bronchoconstriction

and increased vascular permeabilityand increased vascular permeabilityC. Lipoxins.C. Lipoxins. :- Once leukocytes enter tissues, they gradually :- Once leukocytes enter tissues, they gradually

change their major lipoxygenase-derived AA products from change their major lipoxygenase-derived AA products from leukotrienes to anti-inflammatory mediators called lipoxins, which leukotrienes to anti-inflammatory mediators called lipoxins, which inhibit neutrophil chemotaxis and adhesion to endothelium and inhibit neutrophil chemotaxis and adhesion to endothelium and thus serve as endogenous antagonists of leukotrienes.thus serve as endogenous antagonists of leukotrienes.

Anti-inflammatory Drugs That Block Prostaglandin Production Anti-inflammatory Drugs That Block Prostaglandin Production - Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin- Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin99

and ibuprofen, inhibit cyclooxygenase activity, thereby blocking alland ibuprofen, inhibit cyclooxygenase activity, thereby blocking all prostaglandin synthesis (are efficacy in treating pain and fever) prostaglandin synthesis (are efficacy in treating pain and fever) The two inhibitors of the cyclooxygenase enzyme,COX-1 and COX-2.The two inhibitors of the cyclooxygenase enzyme,COX-1 and COX-2.a. COX-1 is produced in response to inflammatory stimuli and also is a. COX-1 is produced in response to inflammatory stimuli and also is

constitutively expressed in most tissues, where it stimulates the constitutively expressed in most tissues, where it stimulates the production of prostaglandins that serve a homeostatic function production of prostaglandins that serve a homeostatic function (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). the gastrointestinal tract).

b., COX-2 is induced by inflammatory stimuli but it is absent from b., COX-2 is induced by inflammatory stimuli but it is absent from most normal tissues Therefore, COX-2 inhibitors have been most normal tissues Therefore, COX-2 inhibitors have been developed with the expectation that they will inhibit harmful developed with the expectation that they will inhibit harmful inflammation but will not block the protective effects of inflammation but will not block the protective effects of constitutively produced prostaglandins.. constitutively produced prostaglandins..

- COX-2 inhibitors may increase the risk for cardiovascular and- COX-2 inhibitors may increase the risk for cardiovascular and1010

cerebrovascular events, possibly because they impair endothelial cerebrovascular events, possibly because they impair endothelial cell production of prostacyclin (PGIcell production of prostacyclin (PGI22), an inhibitor of platelet ), an inhibitor of platelet aggregation, but leave intact the COX-1-mediated production by aggregation, but leave intact the COX-1-mediated production by platelets of TXAplatelets of TXA22, a mediator of platelet aggregation, a mediator of platelet aggregation

c. Glucocorticoids, which are powerful anti-inflammatory agents, act in c. Glucocorticoids, which are powerful anti-inflammatory agents, act in part by inhibiting the activity of phospholipase Apart by inhibiting the activity of phospholipase A22 and thus the and thus the release of AA from membrane lipids. release of AA from membrane lipids.

3. Cytokines 3. Cytokines - Are polypeptide products of many cell types that function as - Are polypeptide products of many cell types that function as

mediators of inflammation and immune responses mediators of inflammation and immune responses - Some cytokines stimulate bone marrow precursors to produce- Some cytokines stimulate bone marrow precursors to produce- - more more

leukocytes, thus replacing the ones that are consumed during leukocytes, thus replacing the ones that are consumed during inflammation and immune responsesinflammation and immune responses

- The major cytokines in acute inflammation are TNF, IL-1, IL-6, and - The major cytokines in acute inflammation are TNF, IL-1, IL-6, and chemokineschemokines 1212

- Cytokines important in chronic inflammation include interferon-γ - Cytokines important in chronic inflammation include interferon-γ (IFN-γ) and IL-12(IFN-γ) and IL-12

A. Tumor necrosis factor and IL-1A. Tumor necrosis factor and IL-1- Their secretion is stimulated by bacterial endotoxin, immune - Their secretion is stimulated by bacterial endotoxin, immune complexes and products of T lymphocytes complexes and products of T lymphocytes - IL-1 is the cytokine induced by activation of the inflammasome. - IL-1 is the cytokine induced by activation of the inflammasome. - The principal role of these cytokines in inflammation is in - The principal role of these cytokines in inflammation is in

endothelial activationendothelial activationBoth TNF and IL-1:Both TNF and IL-1:a. Stimulate the expression of adhesion molecules on endothelial a. Stimulate the expression of adhesion molecules on endothelial

cellscellsb. Enhance the production of additional cytokines notably b. Enhance the production of additional cytokines notably

chemokines) and eicosanoidschemokines) and eicosanoidsc. They may enter the circulation and act at distant sites to inducec. They may enter the circulation and act at distant sites to induce

the systemic acute-phase reactionthe systemic acute-phase reactiond. TNF increases the thrombogenicity of endotheliumd. TNF increases the thrombogenicity of endotheliume. IL-1 activates tissue fibroblasts, resulting in increased e. IL-1 activates tissue fibroblasts, resulting in increased

proliferation and production of ECM. proliferation and production of ECM. B. Chemokines : functions includeB. Chemokines : functions include1. To recruit leukocytes to the site of inflammation 1. To recruit leukocytes to the site of inflammation - Combinations of chemokines that are produced transiently in - Combinations of chemokines that are produced transiently in

response to inflammatory stimuli recruit leukocytes(e.g., response to inflammatory stimuli recruit leukocytes(e.g., neutrophils, lymphocytes or eosinophils) to sites of inflammation :neutrophils, lymphocytes or eosinophils) to sites of inflammation :

2. Some chemokines are produced constitutively in tissues and are 2. Some chemokines are produced constitutively in tissues and are responsible for the anatomic segregation of different cell responsible for the anatomic segregation of different cell populations in tissues (e.g., the segregation of T and B populations in tissues (e.g., the segregation of T and B lymphocytes in different areas of lymph nodes and spleenlymphocytes in different areas of lymph nodes and spleen

c. Activate leukocytes; one consequence of such activation, isc. Activate leukocytes; one consequence of such activation, is

increased affinity of leukocyte integrins for their ligands on endothelial increased affinity of leukocyte integrins for their ligands on endothelial cells cells

d. Two of these chemokine receptors (called CXCR4 and CCR5) are d. Two of these chemokine receptors (called CXCR4 and CCR5) are important coreceptors for the binding and entry of the human important coreceptors for the binding and entry of the human immunodeficiency virus into lymphocytes immunodeficiency virus into lymphocytes

- Chemokines are classified into four groups - Chemokines are classified into four groups - The two major groups are the CXC and CC- The two major groups are the CXC and CCa. CXC chemokines:a. CXC chemokines: Have one amino acid separating the conserved Have one amino acid separating the conserved cysteines and act primarily on neutrophils , IL-8 is typical of this groupcysteines and act primarily on neutrophils , IL-8 is typical of this group b. CC chemokinesb. CC chemokines : Have adjacent cysteine residues and include : : Have adjacent cysteine residues and include :A. Monocyte chemoattractant protein-1 (MCP-1A. Monocyte chemoattractant protein-1 (MCP-1B. Macrophage inflammatory protein-1α (MIP-1α) B. Macrophage inflammatory protein-1α (MIP-1α) - Both (a&b) chemotactic predominantly for monocytes),- Both (a&b) chemotactic predominantly for monocytes),

C. Eotaxin (chemotactic for eosinophils) C. Eotaxin (chemotactic for eosinophils) 4. Reactive Oxygen Species 4. Reactive Oxygen Species : Are synthesized via the NADPH : Are synthesized via the NADPH

oxidase (phagocyte oxidase) pathway and are released from oxidase (phagocyte oxidase) pathway and are released from neutrophils and macrophages, their Functions:neutrophils and macrophages, their Functions:

a. When produced within lysosomes they function to destroy a. When produced within lysosomes they function to destroy phagocytosed microbes and necrotic cells. phagocytosed microbes and necrotic cells.

b. When secreted at low levels, ROS can increase chemokine, b. When secreted at low levels, ROS can increase chemokine, cytokine, and adhesion molecule expression, thus amplifying the cytokine, and adhesion molecule expression, thus amplifying the cascade of inflammatory mediators. cascade of inflammatory mediators.

c. At higher levels, these mediators are responsible for tissue injury c. At higher levels, these mediators are responsible for tissue injury by several mechanisms, includingby several mechanisms, including

1. Endothelial damage and increased permeability1. Endothelial damage and increased permeability2. Protease activation and antiprotease inactivation, with a net 2. Protease activation and antiprotease inactivation, with a net

increase in breakdown of the ECM; and Direct injury to other cellincrease in breakdown of the ECM; and Direct injury to other cell1616

Types (e.g., tumor cells, red cells, parenchymal cells Types (e.g., tumor cells, red cells, parenchymal cells Note:- Fortunately, various antioxidant protective mechanisms(e.g., Note:- Fortunately, various antioxidant protective mechanisms(e.g.,

mediated by catalase, superoxide dismutase, and glutathione) mediated by catalase, superoxide dismutase, and glutathione) 5.Nitric Oxide(5.Nitric Oxide( NO) NO)- Is a short-lived, soluble, free radical gas produced by many cell - Is a short-lived, soluble, free radical gas produced by many cell

types and capable of mediating a variety of functions that include:types and capable of mediating a variety of functions that include:a. In the central nervous system, it regulates neurotransmitter a. In the central nervous system, it regulates neurotransmitter

release as well as blood flowrelease as well as blood flow b. Macrophages use it as a cytotoxic agent for killing microbes and b. Macrophages use it as a cytotoxic agent for killing microbes and

tumor cellstumor cellsc. When produced by endothelial cells, it relaxes vascular smooth c. When produced by endothelial cells, it relaxes vascular smooth

muscle and causes vasodilation. muscle and causes vasodilation. - NO is synthesized de novo from L-arginine, and NADPH by the - NO is synthesized de novo from L-arginine, and NADPH by the

enzyme nitric oxide synthase (NOS).enzyme nitric oxide synthase (NOS).

- There are three isoforms of NOS, - There are three isoforms of NOS, a. Type I, neuronal NOS (nNOS), is constitutively expressed a. Type I, neuronal NOS (nNOS), is constitutively expressed in neurons, and does not play a role in inflammation in neurons, and does not play a role in inflammation b. Type II, inducible NOS (iNOS), is induced in macrophages and endothelial b. Type II, inducible NOS (iNOS), is induced in macrophages and endothelial

cells by a number of inflammatory cytokinescells by a number of inflammatory cytokines and mediators, most notably by IL-1, TNF, and IFN-γ, and is responsible for and mediators, most notably by IL-1, TNF, and IFN-γ, and is responsible for

production of NO in inflammatory reactionsproduction of NO in inflammatory reactions - This inducible form is also present in hepatocytes, cardiac myocytes, and - This inducible form is also present in hepatocytes, cardiac myocytes, and

respiratory epithelial cells respiratory epithelial cells c. Type III, endothelial NOS, (eNOS), is constitutively synthesized primarily c. Type III, endothelial NOS, (eNOS), is constitutively synthesized primarily

(but not exclusively) in endothelium. (but not exclusively) in endothelium. - An important function of NO is as a microbicidal (cytotoxic) agent in activated - An important function of NO is as a microbicidal (cytotoxic) agent in activated

macrophages macrophages - NO plays other roles in inflammation, including:- NO plays other roles in inflammation, including:

-- 1818

Vasodilation and antagonism of all stages of platelet activation Vasodilation and antagonism of all stages of platelet activation (adhesion, aggregation, and degranulation),along with reduction (adhesion, aggregation, and degranulation),along with reduction of leukocyte recruitment at inflammatory sitesof leukocyte recruitment at inflammatory sites

6. Neuropeptides : A6. Neuropeptides : Are small proteins, such as substance P, that re small proteins, such as substance P, that transmit pain signals, regulate vessel tone, and modulate transmit pain signals, regulate vessel tone, and modulate vascular permeability. Nerve fibers that secrete neuropeptides vascular permeability. Nerve fibers that secrete neuropeptides are especially prominent in the lung and gastrointestinal tract.are especially prominent in the lung and gastrointestinal tract.

Il. Il. Plasma Protein-Derived Mediators Plasma Protein-Derived Mediators 1.1. The complement system: Consists of plasma proteins that Upon The complement system: Consists of plasma proteins that Upon

activation, different complement proteins :activation, different complement proteins :a. Coat (opsonize) particles for phagocytosis and destruction,a. Coat (opsonize) particles for phagocytosis and destruction,b. Contribute to the inflammatory response by increasing vascular b. Contribute to the inflammatory response by increasing vascular

permeability and leukocyte chemotaxis. permeability and leukocyte chemotaxis. c. Complement activation ultimately generates a porelike membranec. Complement activation ultimately generates a porelike membrane

attack complex (MAC) that punches holes in the membranes of attack complex (MAC) that punches holes in the membranes of invading microbesinvading microbes

11. Vascular effects: mediated by. Vascular effects: mediated by C3a and C5a: C3a and C5a:a. Increase vascular permeability a. Increase vascular permeability b. Cause vasodilation by inducing mast cells to release histamine b. Cause vasodilation by inducing mast cells to release histamine c. These complement products are called anaphylatoxins because c. These complement products are called anaphylatoxins because

their actions mimic those of mast cells, which main cellular their actions mimic those of mast cells, which main cellular effectors of the severe allergic reaction called anaphylaxis effectors of the severe allergic reaction called anaphylaxis

2. Leukocyte activation, adhesion, and chemotaxis.2. Leukocyte activation, adhesion, and chemotaxis. - C5a, and to lesser extent, C3a and C4a, activate leukocytes - C5a, and to lesser extent, C3a and C4a, activate leukocytes

increasing their adhesion to endothelium, and is a potent. increasing their adhesion to endothelium, and is a potent. chemotactic agent for neutrophils, monocytes, eosinophils, and chemotactic agent for neutrophils, monocytes, eosinophils, and basophilsbasophils

3. Phagocytosis :3. Phagocytosis : When fixed to a microbial surface, C3b acts as an When fixed to a microbial surface, C3b acts as an opsonin and augment phagocytosis by neutrophils and opsonin and augment phagocytosis by neutrophils and macrophages, which express receptors for these complement macrophages, which express receptors for these complement products products

- The MAC, which is made up of multiple copies of the final - The MAC, which is made up of multiple copies of the final omponent C9, kills some bacteria (especially thin-walled omponent C9, kills some bacteria (especially thin-walled eisseriaeisseria) ) by creating pores that disrupt osmotic balance.by creating pores that disrupt osmotic balance.

NOTE- The activation of complement is tightly controlled by cell-NOTE- The activation of complement is tightly controlled by cell-associated and circulating regulatory proteins and tassociated and circulating regulatory proteins and the presence of he presence of these inhibitors in host cell membranes protects normal cells from these inhibitors in host cell membranes protects normal cells from inappropriate damage during protective reactions against microbesinappropriate damage during protective reactions against microbes

- Inherited deficiencies of these regulatory proteins lead to - Inherited deficiencies of these regulatory proteins lead to spontaneous complement activation spontaneous complement activation

1. A protein called 1. A protein called C1 inhibitorC1 inhibitor blocks activation of C1, and its blocks activation of C1, and its inherited deficiency causes a disease called inherited deficiency causes a disease called hereditaryhereditary

angioedemaangioedema, in which excessive to complement activation results in , in which excessive to complement activation results in edema in multiple tissues, including the larynxedema in multiple tissues, including the larynx

2. 2. decay-accelerating factordecay-accelerating factor (DAF) (DAF)- In a disease called - In a disease called paroxysmal nocturnal hemoglobinuria,paroxysmal nocturnal hemoglobinuria, there is there is

an acquired deficiency of DAF that results in complement-an acquired deficiency of DAF that results in complement-mediated lysis of red cells (which are more sensitive to lysis than mediated lysis of red cells (which are more sensitive to lysis than most nucleated cells)most nucleated cells)

1. 1. Kinin system:Kinin system: Its activation leads to the formation of bradykinin Its activation leads to the formation of bradykinin and it causes:and it causes:

a. Increased vascular permeability and arteriolar dilationa. Increased vascular permeability and arteriolar dilationb. Bronchial smooth muscle contractionb. Bronchial smooth muscle contractionc. It causes pain when injected into the skinc. It causes pain when injected into the skinNote : Actions of bradykinin are short –lived because are it is rapidly Note : Actions of bradykinin are short –lived because are it is rapidly

degraded by kininases present in the plasma degraded by kininases present in the plasma 2222

Role of mediators in different reactions of Role of mediators in different reactions of inflammationinflammationvasodilationvasodilation ProstaglandinsProstaglandins

Nitric oxideNitric oxidehistaminehistamine

Increased vascular permeabilityIncreased vascular permeability Histamine and serotoninHistamine and serotoninC3a and C5aC3a and C5aBradykininBradykininLeukotriens C4, D4,E4Leukotriens C4, D4,E4

Leukoyte recruitment and activationLeukoyte recruitment and activation TNF,IL-1TNF,IL-1Chemokines(IL-8)Chemokines(IL-8)C3a& C5aC3a& C5aLTB4LTB4Bacterial productsBacterial products

feverfever IL-1, TNFIL-1, TNFProstaglandin E2Prostaglandin E2

painpain Prostaglandins E2Prostaglandins E2BradykininBradykininneurppeptidesneurppeptides

Tissue damageTissue damage Lysosomal enzymes of leukocytesLysosomal enzymes of leukocytesReactive oxygen speciesReactive oxygen speciesNitric oxideNitric oxide

Anti-inflammatory Mechanisms Anti-inflammatory Mechanisms a. Many of the mediators are short-lived and destroyed by a. Many of the mediators are short-lived and destroyed by

degradative degradative enzymesenzymes..b. here are several mechanisms that counteract inflammatory b. here are several mechanisms that counteract inflammatory

mediators and function to limit or terminate the inflammatory mediators and function to limit or terminate the inflammatory response. response.

a. Some of these, such as lipoxins, and complement regulatory a. Some of these, such as lipoxins, and complement regulatory proteins proteins

b. IL-10: down-regulate the responses of activated macrophages, b. IL-10: down-regulate the responses of activated macrophages, thus providing a negative feedback loop. In a rare inherited thus providing a negative feedback loop. In a rare inherited disease in which IL-10 receptors are mutated, affected patients disease in which IL-10 receptors are mutated, affected patients develop severe colitis in infancy. develop severe colitis in infancy.

c..Other anti-inflammatory cytokines include: TGF-β and tyrosine c..Other anti-inflammatory cytokines include: TGF-β and tyrosine phosphatsephosphatse

CHRONIC INFLAMMATION :CHRONIC INFLAMMATION :Characterized Characterized byLbyLa. prolonged duration (weeks to years) a. prolonged duration (weeks to years) b. Inflammation In which continuing inflammation, tissue injury, and b. Inflammation In which continuing inflammation, tissue injury, and

healingby fibrosis, proceed simultaneously healingby fibrosis, proceed simultaneously c. In contrast to acute inflammation,characterized by infiltration with c. In contrast to acute inflammation,characterized by infiltration with

mononuclear cellsmononuclear cells,, like macrophages, lymphocytes, and plasma like macrophages, lymphocytes, and plasma cells and Repair involving new vessel formation and fibrosis cells and Repair involving new vessel formation and fibrosis

- Acute inflammation may progress to chronic inflammation if the - Acute inflammation may progress to chronic inflammation if the acute response cannot be resolved, either:acute response cannot be resolved, either:

a. Because of the persistence of the injurious agent a. Because of the persistence of the injurious agent b. Because of interference with the normal process of healing, For b. Because of interference with the normal process of healing, For

example, a peptic ulcer of the duodenum initially shows acute example, a peptic ulcer of the duodenum initially shows acute inflammation followed by the beginning stages of resolution, inflammation followed by the beginning stages of resolution, however, recurrent bouts of duodenal epithelial injury interrupthowever, recurrent bouts of duodenal epithelial injury interrupt

this process, resulting in a lesion characterized by both acute and this process, resulting in a lesion characterized by both acute and chronic inflammation chronic inflammation

c. Some forms of injury ( immunologic reactions, some viral c. Some forms of injury ( immunologic reactions, some viral infections) engender a chronic inflammation from the outsetinfections) engender a chronic inflammation from the outset

- - Chronic inflammation may arise in the following settingsChronic inflammation may arise in the following settings:: 1. Persistent infections1. Persistent infections by microbes that are difficult to eradicate. by microbes that are difficult to eradicate. - These include - These include Mycobacterium tuberculosisMycobacterium tuberculosis, , Treponema pallidumTreponema pallidum

(cause syphilis), and certain viruses and fungi all of which tend to (cause syphilis), and certain viruses and fungi all of which tend to establish persistent infections and elicit a T lymphocyte-mediated establish persistent infections and elicit a T lymphocyte-mediated immune response called immune response called delayed-type hypersensitivitydelayed-type hypersensitivity

2. Immune-mediated inflammatory diseases (hypersensitivity 2. Immune-mediated inflammatory diseases (hypersensitivity diseases:diseases: immune reactions develop immune reactions develop against the affected against the affected person's own tissues, leading to person's own tissues, leading to autoimmune diseases a autoimmune diseases a reaction reaction that results in tissue damage and persistent inflammationthat results in tissue damage and persistent inflammation

and autoimmunity plays an important role in several common and autoimmunity plays an important role in several common chronic inflammatory diseases, such as rheumatoid arthritis chronic inflammatory diseases, such as rheumatoid arthritis

- Immune responses against common environmental substances - Immune responses against common environmental substances are the cause of are the cause of allergic diseases,allergic diseases, such as bronchial asthma such as bronchial asthma

- Immune-mediated diseases may show morphologic patterns of - Immune-mediated diseases may show morphologic patterns of mixed acute and chronic inflammation because they are mixed acute and chronic inflammation because they are characterized by repeated boutscharacterized by repeated bouts of inflammation of inflammation In most cases, In most cases, the eliciting antigens cannot be eliminated, these disorders tend the eliciting antigens cannot be eliminated, these disorders tend to be chronic and intractableto be chronic and intractable

3. Prolonged exposure to potentially toxic agents.3. Prolonged exposure to potentially toxic agents. a. Exogenous materials such as inhaled silica a. Exogenous materials such as inhaled silica b. Endogenous agents such as cholesterolb. Endogenous agents such as cholesterol4. Mild forms of chronic inflammation may be important in the 4. Mild forms of chronic inflammation may be important in the

pathogenesis of many diseases such as Alzheimer diseasepathogenesis of many diseases such as Alzheimer disease

., atherosclerosis, type 2 diabetes.., atherosclerosis, type 2 diabetes. Chronic Inflammatory Cells and MediatorsChronic Inflammatory Cells and Mediators1. 1. Macrophages:Macrophages: Are the dominant cells of chronic inflammation Are the dominant cells of chronic inflammation- Are tissue cells derived from circulating blood monocytes after their emigration - Are tissue cells derived from circulating blood monocytes after their emigration

from the bloodstream and are normally diffusely scattered in most connective from the bloodstream and are normally diffusely scattered in most connective tissues and are found in organs that are calledtissues and are found in organs that are called mononuclear phagocyte system mononuclear phagocyte system which include:which include:

a. The liver ( called Kupffer a. The liver ( called Kupffer cells),cells),b. b. Spleen and lymph nodes (where they are called sinus histiocytes)Spleen and lymph nodes (where they are called sinus histiocytes)c. Central nervous system (microglial cells), c. Central nervous system (microglial cells), d. and lungs (alveolar macrophages) d. and lungs (alveolar macrophages) - Macrophages act as filters for particulate matter, microbes as well as the effector - Macrophages act as filters for particulate matter, microbes as well as the effector

cells that eliminate microbes in cellular and humoral immune responsescells that eliminate microbes in cellular and humoral immune responses

- Monocytes arise from precursors in the bone marrow and circulate - Monocytes arise from precursors in the bone marrow and circulate in the blood in the blood for only about a day and ufor only about a day and under the influence of nder the influence of adhesion molecules and chemokines, they migrate to a site of adhesion molecules and chemokines, they migrate to a site of injury within 24 to 48 hours after the onset of acute inflammation injury within 24 to 48 hours after the onset of acute inflammation

- When reach the extravascular tissue, they undergo transformation - When reach the extravascular tissue, they undergo transformation into macrophages, which are larger and have a longer lifespan and into macrophages, which are larger and have a longer lifespan and a greater capacity for phagocytosis than do blood monocytes a greater capacity for phagocytosis than do blood monocytes

- Two major pathways of macrophage activation- Two major pathways of macrophage activation 1. Classical macrophage activation:1. Classical macrophage activation:Is induced by microbial products Is induced by microbial products

such as endotoxin, by T cell-derived signals mainly the cytokine such as endotoxin, by T cell-derived signals mainly the cytokine IFN-γ, and by foreign substances including crystals IFN-γ, and by foreign substances including crystals

- Classically activated macrophages produce lysosomal enzymes, - Classically activated macrophages produce lysosomal enzymes, NO, and ROS, all of which enhance theirNO, and ROS, all of which enhance their ability to kill ingested ability to kill ingested organisms, and secrete cytokines that stimulate inflammationorganisms, and secrete cytokines that stimulate inflammation

2. 2. Alternative macrophage activation: Alternative macrophage activation: Is induced by cytokines other than IFN-γ, Is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytessuch as IL-4 and IL-13, produced by T lymphocytes

- Alternatively activated macrophages are not microbicidal; instead, their role is - Alternatively activated macrophages are not microbicidal; instead, their role is in tissue repair, so they secrete growth factors that promote angiogenesis, in tissue repair, so they secrete growth factors that promote angiogenesis, activate fibroblasts for collagen synthesisactivate fibroblasts for collagen synthesis

NOTE:- In response to most injurious stimuli, macrophages are initially NOTE:- In response to most injurious stimuli, macrophages are initially activated by the classical pathway, designed to destroy theactivated by the classical pathway, designed to destroy the offending agents, offending agents, and this is followed by alternative activation, which initiates tissue repairand this is followed by alternative activation, which initiates tissue repair

Roles of macrophages includeRoles of macrophages include::1. Ingest and eliminate microbes and dead tissues1. Ingest and eliminate microbes and dead tissues , because they respond to , because they respond to

activating signals from T-lymphocytes , they are considered as the most activating signals from T-lymphocytes , they are considered as the most important phagocytes in the cell-mediated arm of adaptive immune responsesimportant phagocytes in the cell-mediated arm of adaptive immune responses

2. Initiate the process of tissue repair and scar formation and fibrosis2. Initiate the process of tissue repair and scar formation and fibrosis

3. 3. Secrete mediators of inflammationSecrete mediators of inflammation, such as cytokines (TNF, IL-1, , such as cytokines (TNF, IL-1, chemokines, and eicosanoids. These cells are therefore central to chemokines, and eicosanoids. These cells are therefore central to the initiation and propagation of all inflammatory responses.the initiation and propagation of all inflammatory responses.

4. Display antigens 4. Display antigens to T lymphocytes and respond to signals from T to T lymphocytes and respond to signals from T cells,cells, thus setting up a feedback loop that is essential for defense thus setting up a feedback loop that is essential for defense against many microbes by cell-mediated immune responses against many microbes by cell-mediated immune responses

B. Lymphocytes: B. Lymphocytes: - Are mobilized in the setting of infections as well as non-immune-Are mobilized in the setting of infections as well as non-immune-

mediated inflammation ( due to ischemic necrosis or trauma), and mediated inflammation ( due to ischemic necrosis or trauma), and are the major drivers of inflammation in many autoimmune and are the major drivers of inflammation in many autoimmune and other chronic inflammatory diseases other chronic inflammatory diseases

- The activation of T and B lymphocytes is part of the adaptive The activation of T and B lymphocytes is part of the adaptive immune response in infections and immunologic diseasesimmune response in infections and immunologic diseases

- In the tissues, B lymphocytes may develop into - In the tissues, B lymphocytes may develop into plasma cells,plasma cells, which secrete antibodies, and CD4+ T lymphocytes are activatedwhich secrete antibodies, and CD4+ T lymphocytes are activated

to secrete cytokinesto secrete cytokines- Due to cytokine secretion, CD4+ T lymphocytes- Due to cytokine secretion, CD4+ T lymphocytes promote promote

inflammation and influence the nature of the inflammatory reaction inflammation and influence the nature of the inflammatory reaction and there are three subsets of CD4+ helper T cells and there are three subsets of CD4+ helper T cells

1. T1. THH1 cells produce IFN-γ, which activates macrophages in the 1 cells produce IFN-γ, which activates macrophages in the classical pathway classical pathway

2. T2. THH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate 2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternativeeosinophils and are responsible for the alternative--. pathway of . pathway of macrophage activation and are important in defense against macrophage activation and are important in defense against helminthic parasites and in allergic inflammation helminthic parasites and in allergic inflammation

- Both T- Both THH1 and T1 and THH17 cells are involved in defense against many 17 cells are involved in defense against many types of bacteria and viruses and in autoimmune diseasestypes of bacteria and viruses and in autoimmune diseases

- Lymphocytes and macrophages interact in a bidirectional way, and - Lymphocytes and macrophages interact in a bidirectional way, and so, they play an important role in propagating chronic inflammationso, they play an important role in propagating chronic inflammation

- Macrophages display antigens to T cells, express membrane - Macrophages display antigens to T cells, express membrane molecules and produce cytokines (IL-12 and others) that stimulate molecules and produce cytokines (IL-12 and others) that stimulate T cell responses and activated T lymphocytes, in turn, produce T cell responses and activated T lymphocytes, in turn, produce cytokines, which recruit and activate macrophages and thus cytokines, which recruit and activate macrophages and thus promote more antigen presentation and cytokine secretion, and the promote more antigen presentation and cytokine secretion, and the result is cellular reactions that sustain chronic inflammation. result is cellular reactions that sustain chronic inflammation.

Eosinophils:Eosinophils:- Are characteristically in parasitic infections and as part of immune - Are characteristically in parasitic infections and as part of immune

reactions mediated by IgE, ed with allergies.reactions mediated by IgE, ed with allergies.- Their recruitment is driven by adhesion molecules similar to those - Their recruitment is driven by adhesion molecules similar to those

used by neutrophils, and by specific chemokines (e.g., eotaxin) used by neutrophils, and by specific chemokines (e.g., eotaxin) - Eosinophil granules contain major basic protein, a cationic protein - Eosinophil granules contain major basic protein, a cationic protein

that is toxic to parasites and causes epithelial cell necrosis. that is toxic to parasites and causes epithelial cell necrosis. D. Mast cellD. Mast cells- As- Are widely distributed in connective tissues throughout re widely distributed in connective tissues throughout

the body and they can participate in both acute and the body and they can participate in both acute and

chronic inflammatory responses and important in allergic chronic inflammatory responses and important in allergic reactions),to environmental antigens.reactions),to environmental antigens.

NOTENOTE: : Although the presence of neutrophils is the hallmark of acute Although the presence of neutrophils is the hallmark of acute inflammation, many forms of chronic inflammation may continue to inflammation, many forms of chronic inflammation may continue to show neutrophilic infiltrates,show neutrophilic infiltrates, as a result of either persistent necrotic as a result of either persistent necrotic cells, microbes or mediators elaborated by macrophages. Such cells, microbes or mediators elaborated by macrophages. Such inflammatory lesions are sometimes called "acute on chronic"-for inflammatory lesions are sometimes called "acute on chronic"-for example, in inflammation of bones (osteomyelitis)example, in inflammation of bones (osteomyelitis)

Granulomatous inflammationGranulomatous inflammation- Is a distinctive pattern of chronic inflammation characterized by - Is a distinctive pattern of chronic inflammation characterized by

aggregates of activated macrophages with scattered lymphocytes. aggregates of activated macrophages with scattered lymphocytes. - Granulomas are characteristic of certain specific pathologic states;- Granulomas are characteristic of certain specific pathologic states;- Consequently, recognition of the granulomatous pattern is - Consequently, recognition of the granulomatous pattern is

important because of the limited number of conditions (some life-important because of the limited number of conditions (some life-threatening) that cause it and causes of granulomas are: threatening) that cause it and causes of granulomas are:

A. Infections: A. Infections: With persistent T-cell responses to certain microbes With persistent T-cell responses to certain microbes (such as(such as Mycobacterium tuberculosis, T. pallidum, Mycobacterium tuberculosis, T. pallidum, or fungi), and or fungi), and Tuberculosis is the prototype of a granulomatous disease caused Tuberculosis is the prototype of a granulomatous disease caused By infection and should always be excluded as the cause when By infection and should always be excluded as the cause when granulomas are identifiedgranulomas are identified

B. Immune mediated Inflammatory disorders like B. Immune mediated Inflammatory disorders like Crohn diseaseCrohn disease C. SarcoidosisC. Sarcoidosis: a disease of unknown etiology : a disease of unknown etiology D. Foreign Bodies: D. Foreign Bodies: Granulomas in response to relatively inert Granulomas in response to relatively inert

foreign bodies ( suture, forming so-called foreign bodies ( suture, forming so-called foreign body granulomasforeign body granulomas NOTE:NOTE:- The formation of a granuloma effectively "walls off" the - The formation of a granuloma effectively "walls off" the

offending agent and is therefore a useful defense mechanism offending agent and is therefore a useful defense mechanism - Granuloma formation does not always lead to eradication of the - Granuloma formation does not always lead to eradication of the causal agent, which is frequently resistant to killing causal agent, which is frequently resistant to killing - Granulomatous inflammation with subsequent fibrosis may be - Granulomatous inflammation with subsequent fibrosis may be

- cause of organ dysfunction in some diseases, like tuberculosis- cause of organ dysfunction in some diseases, like tuberculosisMORPHOLOGY MORPHOLOGY :In the usual H&E preparations::In the usual H&E preparations:a. The activated macrophages in granulomas have pink, granular cytoplasm with a. The activated macrophages in granulomas have pink, granular cytoplasm with

indistinct cell boundaries; called indistinct cell boundaries; called epithelioid cellsepithelioid cellsb. The aggregates of epithelioid macrophages are surrounded by a collar of b. The aggregates of epithelioid macrophages are surrounded by a collar of

lymphocytes and. Older granulomas may have a rim of fibroblasts and connective lymphocytes and. Older granulomas may have a rim of fibroblasts and connective tissue tissue

d. Multinucleate giant cells 40 to 50μm in diameter are found in granulomas.and have d. Multinucleate giant cells 40 to 50μm in diameter are found in granulomas.and have abundant cytoplasm and many nuclei, they derive from the fusion of multiple abundant cytoplasm and many nuclei, they derive from the fusion of multiple macrophages –Langhans cellsmacrophages –Langhans cells

- In granulomas associated with certain infections( tuberculosis) may show a central - In granulomas associated with certain infections( tuberculosis) may show a central zone of necrosis zone of necrosis caseous necrosiscaseous necrosis

- Granulomas associated with Crohn disease, sarcoidosis, tend to be "noncaseating."- Granulomas associated with Crohn disease, sarcoidosis, tend to be "noncaseating."

GranulomaGranuloma

Systemic Effects of inflammationSystemic Effects of inflammation- Called the - Called the acute-phase reaction,acute-phase reaction, - The cytokines TNF, IL-1, and IL-6 are the most important - The cytokines TNF, IL-1, and IL-6 are the most important

mediators of the acute-phase reaction and are released mediators of the acute-phase reaction and are released systemically. systemically.

- TNF and IL-1 have similar biologic actions, although these may - TNF and IL-1 have similar biologic actions, although these may differ in subtle ways .differ in subtle ways .

- IL-6 stimulates the hepatic synthesis of a number of plasma - IL-6 stimulates the hepatic synthesis of a number of plasma proteins. proteins.

The acute-phase response consists of several clinical and pathologic The acute-phase response consists of several clinical and pathologic changes:changes:

a. Fevera. Fever,:,:- Characterized by an elevation of body temperature, Is - Characterized by an elevation of body temperature, Is produced in response to substances called pyrogens that act by produced in response to substances called pyrogens that act by stimulating prostaglandin synthesis in the vascular and stimulating prostaglandin synthesis in the vascular and

perivascular cells of the hypothalamusperivascular cells of the hypothalamus- Bacterial products, such as lipopolysaccharide (LPS) (called - Bacterial products, such as lipopolysaccharide (LPS) (called

exogenous pyrogensexogenous pyrogens), stimulate leukocytes to release ), stimulate leukocytes to release cytokines,such as IL-1 and TNF (called cytokines,such as IL-1 and TNF (called endogenous pyrogensendogenous pyrogens), ), which increase the levels of cyclooxygenases that convert AA into which increase the levels of cyclooxygenases that convert AA into prostaglandins. prostaglandins.

- In the hypothalamus the prostaglandins, especially PGE- In the hypothalamus the prostaglandins, especially PGE22, stimulate , stimulate the production of neurotransmitters, which function to reset the the production of neurotransmitters, which function to reset the temperature set point at a higher level temperature set point at a higher level

NSAIDs, including aspirin, reduce fever by inhibiting cyclooxygenase NSAIDs, including aspirin, reduce fever by inhibiting cyclooxygenase and thus blocking prostaglandin synthesis and thus blocking prostaglandin synthesis

b. b. Elevated plasma levels of acute-phase proteins.Elevated plasma levels of acute-phase proteins. - These plasma proteins are mostly synthesized in the liver, and in - These plasma proteins are mostly synthesized in the liver, and in

the setting of acute inflammation, their concentrations may the setting of acute inflammation, their concentrations may increase several hundred-fold and the best known of these are :increase several hundred-fold and the best known of these are :

1. C-reactive protein (CRP)1. C-reactive protein (CRP)2. Fibrinogen, 2. Fibrinogen, 3. Serum amyloid A (SAA) protein 3. Serum amyloid A (SAA) protein - Synthesis of these molecules by hepatocytes is stimulated by - Synthesis of these molecules by hepatocytes is stimulated by

cytokines, especially IL-6 cytokines, especially IL-6 - CRP and SAA, bind to microbial cell walls, and they may act as - CRP and SAA, bind to microbial cell walls, and they may act as

opsonins and fix complement, thus promoting the elimination of the opsonins and fix complement, thus promoting the elimination of the microbesmicrobes

- Fibrinogen binds to erythrocytes and causes them to form stacks that - Fibrinogen binds to erythrocytes and causes them to form stacks that sediment more rapidly at unit gravity than individual erythrocytes and sediment more rapidly at unit gravity than individual erythrocytes and this is the basis for measuring the , and in erythrocyte sedimentation this is the basis for measuring the , and in erythrocyte sedimentation rate (ESR) as a simple test for the systemic inflammatory response, rate (ESR) as a simple test for the systemic inflammatory response, caused by any number of stimuli, including LPS caused by any number of stimuli, including LPS

- Serial measurements of ESR and CRP are used to assess therapeutic Serial measurements of ESR and CRP are used to assess therapeutic responses in patients with inflammatory disorders responses in patients with inflammatory disorders

- such as rheumatoid arthritis. such as rheumatoid arthritis. - Elevated serum levels of CRP are now used as a marker for - Elevated serum levels of CRP are now used as a marker for

increased risk of myocardial infarction or stroke in patients with increased risk of myocardial infarction or stroke in patients with atherosclerotic vascular disease. atherosclerotic vascular disease.

c. Leukocytosisc. Leukocytosis:: Is a common feature of inflammatory reactions, Is a common feature of inflammatory reactions, especially those induced by bacterial infection especially those induced by bacterial infection

- The leukocyte count usually climbs to 15,000 to 20,000 cells/mL, - The leukocyte count usually climbs to 15,000 to 20,000 cells/mL, but in some extraordinary cases it may reach 40,000 to but in some extraordinary cases it may reach 40,000 to 100,000cells/mL.and These extreme elevations are referred to 100,000cells/mL.and These extreme elevations are referred to as as leukemoid reactionsleukemoid reactions The leukocytosis occurs initially because The leukocytosis occurs initially because of accelerated release of cells byTNF and IL-1) from the bone of accelerated release of cells byTNF and IL-1) from the bone marrow reserve poolmarrow reserve pool. .

- Prolonged infection also stimulates production of colony-- Prolonged infection also stimulates production of colony-stimulating factors (CSFs), stimulating factors (CSFs),

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which increase the bone marrow output of leukocytes, thus which increase the bone marrow output of leukocytes, thus compensating for the consumption of these cells in the compensating for the consumption of these cells in the inflammatory reaction inflammatory reaction

- Most bacterial infections induce an increase in the blood neutrophil - Most bacterial infections induce an increase in the blood neutrophil count, called neutrophiliaViral infections, such as infectious count, called neutrophiliaViral infections, such as infectious mononucleosis, mumps associated with increase numbers of mononucleosis, mumps associated with increase numbers of lymphocytes (lymphocytosis).lymphocytes (lymphocytosis).

- Bronchial asthma and parasite infestations all involve an increase - Bronchial asthma and parasite infestations all involve an increase in the absolute number of eosinophils, creating an eosinophiliain the absolute number of eosinophils, creating an eosinophilia

- Typhoid fever , rickettsiae, and certain protozoa) are associated - Typhoid fever , rickettsiae, and certain protozoa) are associated with a decreased number of circulating white cells (leukopenia)with a decreased number of circulating white cells (leukopenia)

- Rigors (shivering)and chills Chills (perception of being cold - Rigors (shivering)and chills Chills (perception of being cold