PATH*3610: Units 3, 4

acute inflammation

first line of defense against injury; redness, heat, swelling, pain, loss of function; changes occurring in blood vessels leads to leakiness of vessels; fluid, chemical mediators, and leukocytes move into tissue to destroy causative agent and remove debris

two major components of acute inflammation

• vascular changes: vessels dilate to increase blood flow to the area and vessels become more permeable to allow plasma proteins to leave circulation and enter injured site

• cellular response: emigration of leukocytes from microcirculation to site of injury

vascular injury 

due to inflammation; occurs in microcirculation; transient vasoconstriction first; marked dilation of arterioles, capillaries, and venules caused by release of a variety of chemical mediators from damaged and necrotic cells (vasoactive amines, kinins)

histamine

derivative of histadine; released by mast cells; causes capillary dilation

mast cells

found throughout body but mainly in damaged and necrotic cells in the vicinity of capillaries; contain histamine granules; injury to surface or activation causes degranulation, leading to capillary dilation

hyperemia

increased flow of blood in tissue; caused by arteriolar dilation

what causes increased permeability of vessels

• histamine widens intracellular junctions

• direct injury to endothelium results in necrosis, detachment, and leakage of plasma

• neutrophil release of proteolytic enzymes and toxic oxygen species leading to endothelial cell injury and detachment

• increased transcytosis via vesicles

• immaturity in blood vessels

exudation

process of increased movement of fluid, larger protein molecules, and cells out of vasculature due to increased permeability; causes swelling and accumulation of inflammatory exudate

stasis

slower flood of blood; occurs as fluid moves into interstitial space so blood becomes more viscous

exudate

the fluid that leaves permeable vessels and forms in tissues or tissue surfaces; like plasma in composition; may contain RBCs, WBs, proteins

transudates

ultrafiltrate of plasma; big molecules are held back by the capillary wall; osmotic gradient develops; small protein molecules can exit capillary and return to vasculature via lymphatics

cycle of inflammation with exudate

movement of large molecules from plasma to interstitium decreases osmotic pressure effect of the plasma proteins; favour fluid remaining in the interstitium leading to further swelling; at some point, increased tension in tissues limits further exudation

characteristics of exudate: circumstances of formation, protein content, protein type, cells, appearance

• form with increased vascular permeability (inflammation)

• high protein content

• various proteins (albumins, globulins, fibrin)

• cells: numerous, neutrophils dominate

• turbid, yellow/white, pink

characteristics of transudate: circumstances of formation, protein content, protein type, cells, appearance

• form with normal vascular permeability (increased vascular HP, decreased oncotic)

• low protein content

• mostly albumin

• cells: few, healthy

• clear, colourless

benefits of exudation

dilutes offending agents, brings defensive proteins into area, increases drainage of area via lymphatics; takes agents to lymph nodes for protective immune response

fibrin

large protein found in exudate; formed from fibrinogen from liver; contributes to osmotic pressure; leaves capillaries when permeability is increased and is converted in tissues to fibrin via tissue thrombin; pink-staining meshwork; localizes inflammatory process and provides meshwork for neutrophil movement

thromboplastin

precursor for thrombin; released by tissue injury so many injuries that initiate inflammation also initiate fibrin formation

coagulation factor XIII

converts monomeric fibrin to insoluble fibrillary polymer

shipping fever

lobar pneumonia in cattle caused by infection with bacteria mannheimia hemolytica; causes abundant fibrin production within lung and on pleural surface where it can cause adhesions between pleura of lung and that lining the ribcage

inflammatory cells

white blood cells; derived from myeloid cell line, move into bloodstream when mature; mononuclear cells and granulocytes

granulocytes

have a multilobulated nucleus and contain cytoplasmic granules; neutrophils, basophils, eosinophils

neutrophils

greatest role in acute inflammation, highest numbers in early stages, actively motile, capable of phagocytosis, contain enzymes that can degrade biologic material

eosinophils

contain enzymes and granules; recruited to fight parasites; involved in hypersensitivity responses

neutropenia

low numbers of neutrophils; seen as side effect of cancer therapy due to cytotoxic drugs or radiation therapy; increased risk of infection

mononuclear cells

smoothly outlined, rounded nucleus; lymphocytes, plasma cells, monocytes, macrophages; greater role in more chronic stages of inflammation

macrophages

greatest role in acute inflammation for mononuclear cells; phagocytes; ingest microorganisms and clean up cellular debris; secrete substances such as endogenous pyrogen and complement components

summary steps for leukocyte recruitment

1. margination, rolling, and adhesion of leukocytes

2. transmigration of leukocytes

3. chemotaxis

4. leukocyte activation

5. phagocytosis and pathogen degradation

leukocyte recruitment: margination, rolling, and adhesion of leukocytes

1. microvasculature dilates and becomes leaky in acute inflammation

2. rate of blood flow within vessel slows

3. normal laminar flow of blood constituents becomes disordered

4. WBCs tend to move out toward vessel wall as opposed to moving centrally

5. marginated leukocytes roll along surface, weakly sticking in place with selectins

6. selectins are up-regulated by inflammatory mediators

7. integrins on endothelial cells allow leukocytes to adhere firmly to vessel wall

selectins used in adhesion

L-selectins for leukocytes, P-selectins for platelets

leukocyte recruitment: transmigration of leukocytes

1. after adhesion, neutrophils leave vessel by squeezing between intracellular junctions (diapedesis); facilitated by PECAM-1

2. pass through basement membrane by degrading them with secreted collagenases

3. move into tissue spaces (interstitium)

definition of chemotaxis

process by which inflammatory cells are attracted to an area of injury by directional migration along a chemical concentration gradient (complement factors C3a, C5a, leukotriene, cytokines, exogenous substances)

leukocyte recruitment: chemotaxis

1. chemotactic molecules bind to receptors on leukocyte surfaces

2. increases intracellular calcium

3. triggers assembly of intracellular contractile elements

4. allows leukocytes to move by extending pseudopods

5. chemotactic molecules also activate leukocytes

leukocyte recruitment: leukocyte activation

PAMPs are recognized by TLRs; activates leukocytes and starts inflammatory response; leads to phagocytosis, upregulation of mechanisms for degradation and killing of microbes, and production of inflammatory mediators

leukocyte recruitment: phagocytosis and pathogen degradation

phagocytic cells recognize opsonized particles or agents and attach to them; forms a phagosome; stimulates sudden increase in oxygen-dependent metabolism in leukocytes; produces ROS to kill pathogens; pathogens are further degraded by fusion of phagosome with lysosomes that release acid hydrolases

inflammatory exudate

characterized by presence of inflammatory cells; opaque or cloudy appearance

mediators of acute inflammation

chemicals derived from either plasma or cells; in plasma, they are inactive precursors that are activated via enzymes; mediators are either preformed and stored in cytoplasmic granules or formed when required; bind to receptors on cells to release further mediators

major groups of inflammatory mediators

vasoactive amines, plasma proteases, lysosomal constituents, arachidonic acid metabolism, platelet-activating factor, cytokines

inflammatory mediators: vasoactive amines

histamine and serotonin (from platelet aggregation); cause vasodilation and increased permeability; greatest role of inflammatory mediators in causing immediate phase of the acute inflammatory response

inflammatory mediators: plasma proteases

plasma-derived factors activated by factor XII during endothelial injury; kinin system, coagulation cascade, complement system

kinin system

produces bradykinin that causes increased vascular permeability and mediates pain; precursor kininogen is cleaved by enzyme kallikrein, which is produced via XIIa on precursor prekallikrein

coagulation cascade

factor XIIa activates thrombin to produce fibrin; fibrin is broken down to produce fibrinopeptides which increase vascular permeability and are chemotactic for neutrophils; thrombin also enhances leukocyte adhesion to endothelial cells

complement system

C5a and C3a stimulate histamine release from mast cells, increasing vascular permeability; C5a acts as a chemotactic agent and activator for phagocytic cells; C3b acts as an opsonin; C5a activates lipooxygenase pathway of arachidonic acid metabolism

inflammatory mediators: lysosomal constituents

neutrophils generate free radicals that cause endothelial damage to increase vascular permeability; also kill and degrade microorganisms

inflammatory mediators: arachidonic acid metabolism

phospholipases release arachidonic acid from cell membranes of inflammatory cells; reactions produce prostaglandins, leukotrienes, liposins (eicosanoids); synthesis is increased at inflammatory sites

inflammatory mediator: platelet-activating factor

generated from cell membranes of neutrophils, monocytes, endothelium platelets, etc. by action of phospholipase A; cause platelet aggregation and activation, vasodilation, increased vascular permeability at low levels, vasoconstriction at high levels

inflammatory mediators: cytokines

polypeptide products of activated lymphocytes and macrophages; modulate functions of other cells; colony-stimulating factors, growth factors, interleukins, chemokines; produced during inflammatory and immune responses; two most important are IL-1 and TNF

IL-1 and tumor necrosis factor (TNF)

cytokines produced by activated macrophages, dendritic cells, and T-lymphocytes; secretion stimulated by inflammatory mediators and injurious stimuli; induce endothelial activation to express selectins and integrins; activate tissue fibroblasts (IL-1) and neutrophils (TNF); induce systemic acute-phase responses

anti-inflammatory agents

suppress response to an injurious agent; used for swelling of spinal cord after intervertebral disc protrusion; non-steroidal anti-inflammatory drugs and corticosteroids

non-steroidal anti-inflammatory drugs (NSAIDs)

aspirin, ibuprofen, naproxen; inhibit conversion of arachidonic acid to prostaglandins and have anti-inflammatory and analgesic activity; first choice for treatment of chronic inflammatory diseases or mild to moderate pain

corticosteroids

synthetic glucocorticoids to suppress inflammatory response; block production of arachidonic acid; diminish vasodilation and decrease permeability; stabilize lysosomal membranes of inflammatory cells; may suppress immune response; prednisone, dexamethasone, bethamethasone

clinical signs of acute inflammation: localized pain

pain from injury and inflammatory response; caused largely by mediators of inflammation in arachidonic cascade; polypeptides of low molecular weight (bradykinin, histamine, serotonin) signal pain through changes in vascular permeability; bradykinin is the main moderator of pain sensation through nerve endings; increase in tissue tension

systemic signs of inflammation

fever, malaise, hypothermia, changes in peripheral WBC count, changes in plasma proteins

systemic signs of inflammation: fever and hypothermia

elevation of body core temp; pyrogens can be endogenous or exogenous; endogenous pyrogens in acute inflammation are IL-1 and IL-6; enter blood circulation from site of inflammation and travel to brain where they act at hypothalamus via prostaglandin synthesis to reset body temp

systemic signs of inflammation: changes in peripheral WBC count

increased total WBC count (leukocytosis); may have neutrophilia of even immature neutrophils- extent tells us severity of inflammation; release of leukocytes from bone marrow is mediated by TNF and IL-1; neutrophilia may not be detected if inflammation is so severe that neutrophils go directly to injured area

systemic signs of inflammation: changes in plasma proteins

acute phase reaction; include C-reactive protein, fibrinogen, haptoglobin, alpha 1-antitrypsin; increased levels of these substances in plasma can be detected and are a nonspecific indication of presence of inflammation

pus

liquefied mass of necrotic tissue, dead organisms, neutrophils

abscess formation and inflammation

may form when an area of suppurative inflammation becomes walled off by fibrous tissue; area is often red, warm, swollen, painful to touch; cause fever, loss of appetite; may rupture and heal; if the abscess ruptures but does not drain properly, it may reform

worst case scenario for abscesses

bacteria escapes the site, causing local spread of infection (cellulitis) or systemic spread of infection (sepsis)

sepsis after abscesses

spread of bacteria and/or toxins into the bloodstream; causes marked widespread cytokine release; if antibiotic therapy and medical support don’t work, DIC, shock and metabolic disturbances cause death

chronic inflammation

large amount of mononuclear cell types instead of neutrophils; result of a continued inflammatory response in combination with an immune response against a persistent injurious agent; accumulation of activated T cells, plasma cells, macrophages; fibrosis occurs

what is chronic inflammation characterized by

• some degree of immune response with mononuclear cells

• infiltration and accumulation of macrophages

• healing of tissue through development of granulation tissue, characterized by fibrosis and angiogenesis

• ongoing tissue injury and necrosis

tuberculosis

causes chronic inflammation; systemic signs are often chronic - fever, weight loss, fatigue; local signs are coughing and hemoptysis; necrosis and chronic inflammation of lung tissue; granulomatous inflammation

granulomatous inflammation

specific type of chronic inflammation characterized by epithelioid cells; active T cell mediated immune response must occur; limited number of conditions that cause it

epithelioid cells

activated macrophages which have a large amount of foamy pale cytoplasm due to presence of secretory rough ER; resemble squamous epithelial cells; have increased ability to secrete lysozyme and other enzymes; not as efficient as phagocytosis

immune response for granulomatous inflammation

effector T cells produce lymphokines that inhibit migration of macrophages, forming granulomas; macrophages accumulate with the live bacteria inside, forming the tubercles or granulomas that characterize the disease

differential diagnoses for granulomatous inflammation

• atypical bacteria (mycobacteria spp., treponema pallidum, brucella spp.)

• fungal pathogens within tissues (pulmonary blastomycosis)

• parasites in tissues (lungworms)

• inert foreign bodies (embedded plant material)

• immune-mediated diseases (crohn’s disease)

why does granulomatous inflammation develop

when phagocytosis and destruction of a causal agent by macrophages is impaired; the causal agent can be phagocytosed but survive and persist within macrophages; or when phagocytosis of a causal agent is impaired

leprosy

caused by mycobacteria leprae; skin lesions and involvement of peripheral nerves occurs; strong T cell response develops granulomas; poor T cell response would make bacillus multiply in macrophages and accumulate in tissues; causes nodular skin thickening, extensive tissue destruction, lesions of finger and face

tissue affects of granulomatous inflammation

granulomas are initially microscopic and enlarge with time; functional tissue around it is lost due to necrosis and replaced by scar tissue; caseous necrosis may occur; adjacent granulomas form large masses

foreign body granulomas

develop and inert and non-antigenic foreign material enters tissue and is too large to be phagocytosed by single macrophage; macrophages gather around it and attempt to remove it by nonimmune phagocytosis; rarely clinically significant unless they obstruct organ function

furunculosis

ingrown hair; keratin is not recognized by immune system as self-proteins; if large quantities are embedded within tissues, they induce a foreign body reaction leading to local granulomatous response

non-granulomatous chronic inflammation

any chronic inflammation not characterized by epithelioid cells; characterized by presence of sensitized lymphocytes, plasma cells, macrophages scattered through affected tissue, areas of necrosis and fibrosis

causes of non-granulomatous chronic inflammation

• chronic viral infections

• other chronic infections

• chronic autoimmune diseases

• allergic conditions and parasitic infections

• chronic toxic disease

causes of non-granulomatous chronic inflammation: chronic viral infections

evoke B and T cell response leading to necrosis of affected cells; tissue reaction characterized by presence of lymphocytes, plasma cells, necrosis, repair

causes of non-granulomatous chronic inflammation: other chronic infections

microorganisms that survive in macrophages once phagocytosed but induce ineffective T cell response; foamy macrophages accumulate in tissue without forming granulomas; contain large numbers of organism in cytoplasm

causes of non-granulomatous chronic inflammation: chronic autoimmune diseases

ineffective T cell response directed against a self antigen; foamy macrophages accumulate in tissue; rheumatoid arthritis, chronic ulcerative colitis

causes of non-granulomatous chronic inflammation: allergic conditions and parasitic infections

eosinophils and mononuclear cells accumulate in tissues affected by repeated or chronic acute hypersensitivity reactions; also associated with metazoal parasites (bronchial asthma, nematodes, trematodes)

causes of non-granulomatous chronic inflammation: chronic toxic disease

chronic alcohol consumption can cause necrosis of liver and pancreas cells, causing them to become antigenic; immune response occurs dominated by necrosis and fibrosis; mononuclear cell infiltration may be mild

names for mixed acute and chronic inflammation

chronic active, recurring acute, subacute, and chronic suppurative inflammation

chronic suppurative inflammation

develops when the body is unable to clear a strong pyogenic stimulus; appears as an area of necrosis, pus, fibrosis, infiltration of mononuclear cells; fibrosis may become a prominent features; thick fibrous walls delineating areas of suppurative inflammation and necrosis

abscess

roughly round cyst-like structure with thick fibrous white walls and central cavity filled with pus, necrotic debris, fibrin

osteomyelitis

result of infection of bone with pyogenic bacteria; hematogenous osteomyelitis or secondary osteomyelitis; progresses to chronic phases more than other pyogenic bacteria infections due to rapid tissue necrosis because of ischemia and abscesses; results in formation of sequestrum; difficult to resolve because of ischemia

sequestrum

fragment of devitalized bone that persists despite attempts of inflammatory response to clear it

hematogenous osteomyelitis

bacteria enters bloodstream through a wound in skin or subcutaneous tissues in GI tract (infectious enteritis, colitis) or umbilicus; in growing children, epiphyseal cartilage has abundant blood supply that predisposes site to osteomyelitis

secondary osteomyelitis

bacteria develop secondary to extension from a wound or adjacent site of infection; occurs secondary to implantation of bacteria into bone through an open fracture site, orthopedic surgery incision, or extension from adjacent cellulitis

anemia of chronic inflammation

systemic sign of chronic inflammation; non-regenerative; caused by inflammatory mediators (cytokines); result in reduced transport of stored iron into plasma despite normal iron stores so hemoglobinization is inadequate and anemia results

treatment of chronic suppurative inflammation

often poorly responsive to antibiotic therapy; large amounts of pus and ischemia makes it inaccessible to host defense mechanisms and antimicrobial drugs

amyloidosis

group of diseases characterized by the deposition of amyloid in interstitium of tissues

causes of amyloidosis

• chronic inflammation

• combination of chronic inflammatory and immune conditions (rheumatoid arthritis, ulcerative colitis)

• genetic conditions where inflammation is excessive

• production of amyloid protein in tumours

amyloid

beta-pleated fibrillar protein; abnormally folded and insoluble; consistent structural orientation; microscopically appears as amorphous eosinophilic (pink staining); underlying chemical structure depends on source of precursor protein; fifteen forms have been identified

three most common amyloid proteins

AA amyloid, AL amyloid, amyloid AB

AA amyloid protein

derived from serum amyloid-associated, non-immunoglobulin protein; produced by liver during inflammatory processes as part of acute phase response; explains presence of amyloid in association with some chronic inflammation

AL amyloid protein

derived from immunoglobulin light chains produced by some plasma cell or B cell tumours

amyloid Aβ protein

characterizes cerebral plaque lesions of alzheimers

how do we classify amyloidosis

biochemical composition, type of amyloid produced, and tissue or organ distribution; systemic, localized, and familial

systemic amyloidosis

involvement of several organ systems; divided into primary and secondary types

primary systemic amyloidosis

most common; AL type; associated with multiply myeloma and malignant neoplasm of plasma cells; abnormal plasma cells may secrete only light chain subunit of immunoglobulin; have a role in AL formation

secondary systemic amyloidosis

reactive; amyloid depositions which occur widely in the body often in association with chronic inflammatory diseases; tuberculosis, chronic osteomyelitis, autoimmune disease

localized amyloidosis

localized amyloid depositions within a single tissue organ; associations found between alzheimer’s and amyloid in the brain; also seen in some endocrine tumors derived from precursor molecules of peptide hormones; local amyloid deposits are also associated with local plasma cell tumours

familial amyloidosis

rare, inherited disorders where amyloid is deposited locally in organs such as heart, kidney, nervous tissue