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Flashcards in Block 1 Deck (110)
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1
Q

Describe the basic procedure of an autopsy

A

• External examination

o Rigor mortis

o Liver mortis (color change)

o Algor mortis (temperature change)

o Assess injuries, identifying features, evidence of medical intervention

  • Internal examination and evisceration
  • Neuropathologic exam
  • Microscopic exam
  • Ancillary testing (case-by-case)
2
Q

List the manners of death

A

Definition: Based on circumstances surrounding death (vs. COD, an injury or disease resulting in death)

  • Suicide
  • Homicide
  • Accident
  • Undetermined
  • Natural
3
Q

Recognize deaths that fall outside of a physician’s jurisdiction

A

Coroner case

oCoroners and medial examiners certify deaths with non-natural MOD oReferred when death is/of:

  • <24 hrs hospital admission
  • Under anesthetic
  • Violent death (even after hospital stay)
  • After in-hospital accident
  • Prisoners
  • Infant sudden death
  • Unidentified person

Medical case

o Physicians can certify deaths with natural MOD

4
Q

Distinguish between mechanism of death and cause of death

A

MOD: circumstances surrounding death

•COD: injury or disease producing physiologic derangement in body leading to death

o Etiologically specific

o If non-natural, the MOD is then also non-natural (coroner assumes jurisdiction)

• OSC (other significant conditions): contributed to death, but distinct from major COD

5
Q

Define Hyaline change

A

describes a glassy pink appearance, usually from protein accumulation (ex. Amyloids, Russell bodies)

6
Q

define anthracosis

A

black discoloration of lung tissue and draining lymph nodes from inhaled and phagocytosed carbon

7
Q

Define caspase

A

cysteine proteases, exist as pro-enzymes and activate apoptosis cascade when cleaved

8
Q

List the types of intracellular accumulations and give examples of each, including morphologic descriptions.

A

•Lipids:

oSteatosis: accumulation of TAGs

  • Common in liver
  • Round, clear spaces in cytoplasm

oAtherosclerosis: accumulation of cholesterol in smooth muscle cells

  • Intracellular: look foamy
  • Extracellular: crystallizes, looks like shards

•Proteins

oAppear pink, many different shapes possible

oAmyloidosis: if proteins fold abnormally and deposit

  • Usually extracellular
  • Appear glassy, pink, “hyaline”
  • Non-branching fibrils, bound by congo red stain

•Hyaline Change

oDescribes a glassy pink appearance, usually from protein accumulation (ex. Amyloids, Russell bodies in plasma cells)

•Glycogen

oClear cytoplasmic vacuoles, can appear in nucleus in liver cells

•Pigments

oCarbon: black (anthracosis)

oLipofuscin: brown-yellow, granular, cytoplasmic; from incomplete breakdown of subcellular components

oMelanin: brown-black, from melanocytes

oHemosiderin: golden yellow-brown, granular, from iron bound to ferritin

oBilirubin: yellow, from hemoglobin

9
Q

Explain the difference between apoptotic and necrotic cell death.

A

•Apoptotic

o Physiologic or pathologic

o No inflammation

o Membranes intact

o Cell shrinkage

•Necrotic

o Pathologic

o Inflammation

o Membranes disrupted

o Cell swelling

10
Q

Describe the extrinsic and intrinsic pathways of apoptosis, and know the names of the major components involved in each.

A

•Initiation phase can be intrinsic or extrinsic

•Intrinsic pathway (mitochondrial)

o Normally, balance between pro- and anti-apoptotic proteins (Bcl family)

o Signal: irradiation, lack of survival signals

o Cause pro-apoptotic proteins to dominate

o Forms channel in mitochondrial membrane

o Release of contents (cytochrome c)

o Cytochrome c activates caspases, which activate cascade

•Extrinsic pathway (death receptor)

o T lymphocytes express FasL molecule on membrane

o FasL binds Fas receptor on cell (a death receptor)

o Causes caspase cleavage and activation of cascade •

COMMON: Execution phase

o DNA fragmentation, endonuclease activation. cytoskeleton breakdown

o Membrane blebs into Apoptotic Body

o Phagocytosed

11
Q

Explain the role of ATP depletion in the major mechanisms of cell damage

A

o Na+/K+ pump fails, leads to cell swelling

o Switch to anaerobic metabolism, leads to lactic acid accumulation and decreased pH

o Ca2+ pump fails, leads to influx of Ca2+

o Damaged/degradation of protein synthesis apparatus

• Ribosomes detach from RER

o Abnormal protein folding

12
Q

Describe the morphologic changes associated with apoptosis

A

o Cell shrinkage, darkly stained cytoplasm

o Nuclear pyknois

o Cytoplasmic blebs

o Apoptotic bodies rapidly phagocytosed

13
Q

Describe the morphologic changes associated with reversible necrotic cell death

A

oElectron microscope

  • Membrane blebbing, loss of microvilli
  • Mitochondrial swelling
  • ER dilation

oLight microscope

  • Cell swelling, clear vacuoles
  • Fatty change
14
Q

Describe the morphologic changes associated with irreversible necrotic cell death

A

oElectron microscope

  • Membranc discontinuity
  • Greater mitochondrial swelling
  • Myelin figures (whorled phospholipids from membranes)

oLight microscope

  • Cytoplasmic eosinophilia (dark pink cytoplasm)
  • Dystrophic calcification (fatty acid calcification)
  • Nuclear changes (karyolysis, pyknosis, karyorrhexis, loss of nucleus)
15
Q

Types of Necrosis

A
  • Coagulative necrosis— often with ischemia, dead tissue architecture maintained
  • Liquefactive necrosis— often with bacterial and fungal infections, hypoxic damage in CNS; dead cells completely digested leaving only liquid
  • Fat necrosis— often in pancreatitis; FA’s combine with calcium, makes chalky white areas
  • Caseous necrosis— often in tuberculosis infection; tissue is “cheesy” granular material
16
Q

Pyknosis

A

chromatin condensation (darkening) and breaking up into fragments

17
Q

Karyorrhexis

A

chromatin fragmentation

18
Q

Karyolysis

A

fading of chromatin

19
Q

Types of calcification

A

•Dystrophic calcification—calcium deposition in dying tissues; can occur with normal Ca2+ levels; appears dark blue-purple (basophilic) & variable shape, both intra- and extra-cellular. Also in areas of atherosclerosis.

•Metastatic calcification—when high serum Ca2+, occurs in otherwise normal (not damaged/dead) tissue. Appears same as dystrophic under light microscope.

20
Q

Define inflammation

A
  • Reaction to injurious agent that limits damage and promotes repair
  • See rubor/redness, tumor/swelling, calor/heat, and dolor/pain
  • Mediated by vessels and blood cells
  • Tightly regulated chain of molecular and cellular events
  • Acute or chronic by duration of response and types of cells involved
21
Q

Describe the difference between innate and acquired immunity

A

Innate

o Non-specific defense mechanisms

o Barriers (skin, pH) and inflammation

Acquired

o Response to specific injurious agent

o Mediated by antibodies

o “immune” system

22
Q

Neutrophils/ Polymorphonuclear leukocyte (PMN)

A

o Most numerous cells in peripheral blood (50-70%)

o Segmented nucleus with 3-5 lobes

o Pseudopods—moves to site of injury

o Granules (lysosomes)

o Motile phagocyte

o Primary cell responder in acute inflammation

23
Q

Lymphocytes

A

o Single nucleus, scant cytoplasm

o Includes: B cells, T cells, NK cells

o Produce antibodies, cytokines, or toxic granules to eliminate foreign invaders

o Primary cell in chronic inflammation

24
Q

Monocytes (circulating) /Macrophages (when in tissues)

A

o Produced in bone marrow, move to tissues after few days in circulation

o Horseshoe nucleus, granules

o Motile phagocyte

o Recognizes foreign material when opsonized

o Presents antigens via Class II MHC receptors

o Helps transition between innate to acquired immunity

25
Q

Eosinophils

A

o Bi- or tri-lobed nucleus

o Cytoplasm filled with pink granules

• Contain numerous mediators of inflammation: Histamine, proteolytic enzymes and major basic protein

o Involved in inflammatory reactions to allergens and parasites

26
Q

Basophils/Mast Cells

A

o Bilobed nucleus (but often obscured)

o Cytoplasm filled with blue/basophilic granules: Histamine, proteoglycans, proteolytic enzymes, lipid mediators of inflammation

o Analogous cells in tissues = “mast cells”

27
Q

Platelets

A

o Anuclear fragments of megakaryocyte cytoplasm

o Contain RNA, mitochondria, canalicular system and granules of platelet activating factor (stimulates inflammation)

o Primary “cells” in blood clot formation

28
Q

List the classes of chemical mediators of inflammation.

A

•Plasma derived (in precursor forms)

o Factor XII (Hageman factor)

o Complement proteins

o Kinins

o Clotting proteins

•Cell derived (in organelles or produced when stimulated)

o Vasoactive amines (histamine, serotonin)

o Arachidonic acid metabolites (prostaglandins, leukotrienes, lipoxins)

o Cytokines and chemokines

o Nitric oxide

o Lysosomal contents

o Oxygen-derived free radicals

29
Q

Define acute and chronic inflammation.

A

•Acute

o Immediate response but short duration

o Changes in blood vessels so WBCs move into tissues where they neutralize injurious agent

o Important cells: granulocytes (primarily neutrophil)

Chronic

o Prolonged onset, prolonged duration

o Usually follows acute inflammation, but may begin insidiously and asymptomatically

o Important cells: mononuclear (lymphocytes, macrophages, plasma cells)

30
Q

Describe the processes involved in tissue homeostasis

A
  • Maintain normal cell population:
  • Rate of cell proliferation: regenerates lost tissue mass
  • Rate of cell death by apoptosis: eliminates damaged cells
  • Rate of cellular differentiation: regulates cell population size
31
Q

Define regeneration and distinguish it from repair

A

Regeneration restores damaged or lost cells/tissues to their original state

o Via cell proliferation from remaining cells or stem cells

o Requires ECM scaffold

o Ex. Hematopoietic system, skin and GI epithelium

Repair involves a combination of regeneration and scar formation by collagen deposition

o Requires cell proliferation from parenchyma or stem cells

o ECM is usually damaged so new ECM is deposited

o Ex. Healing of a burn

32
Q

Describe the components of the cell cycle

A

• Cycle regulated by cyclin and cdk (cyclin dependent kinases) dimer
• Phosphorylate Rb (retinoblastoma protein) which releases inhibition
o Allows transcription to occur (S phase)
• Interphase
o G1: cells prepare for DNA synthesis, but not yet committed to replication
• Checkpoint (G1/S): checks for DNA integrity
o S: DNA synthesis, cell now committed to replicate or die
• Checkpoint (S/G2): checks for damaged or unduplicated DNA
o G2: cell prepares to enter mitosis
• Mitosis
o Prophase, metaphase, anaphase, telophase
• Cell types
o Labile cells: continually dividing
• Epidermis, GI tract epithelium
o Quiescent cells: stable cells; low level of replication, in G0 stage
• Have potential to reenter cell cycle
• Hapatocytes
o Permanent cells: have left the cell cycle
• Neurons, cardiac myocytes

33
Q

Define and explain the various types of stem cells

A

• Population of cells that have not terminally differentiated and can regenerate lost cells
o Self renewal (one progeny remains a stem cell after cell division)
o Asymmetric replication (other progeny differentiates)
• Types
o Embryonic
• Derived from inner cell mass of blastocyst
• Each cell is pluripotent
• Have self renewal capacity
• Potential use to treat diseases with loss of critical cell type (ex. MI)
Challenges
• Ethical issues
• Transplant rejection
• Tumor formation (teratomas)
• Persistence of underlying disease
• Making differentiated cells function normally
o Induced pluripotent stem cells (iPS)
o Adult
• Some tissues have a reservoir of self-renewing cells
• Hair follicle, intestinal crypts, skin
• Restricted in their differentiation potential
• Restricted niches (location)
• But can transdifferentiate in vitro
• Function to regenerate cells lost by normal wear and tear
• Response post-injury
• Increase # dividing stem cells
• Increase # replications of cells
• Decrease cell-cycle time for each division
o Cancer stem cell

34
Q

List the functions of the extracellular matrix.

A

o Provides turgor by sequestering water, or rigidity by sequestering minerals
o Reservoir for secreted growth factors
o Framework for cells to adhere, migrate, and proliferate
o Mediates cell-cell interactions
o Site of remodeling during wound healing

35
Q

List the components of the extracellular matrix

A

Fibrous structural proteins

Collagen

Elastin and fibrillin

Cell adhesion proteins

  • Secreted: fibronectin and laminin
  • Cell-surface bound: integrins and cadherins
  • Function as receptors, allow cells to interact with each other and ECM

Proteoglycans and hyaluronic acid

36
Q

Distinguish between the interstitial matrix and basement membranes.

A

• Two types of ECM
• BOTH: made of fibrous structural proteins, adhesive glycoproteins, proteoglycans and hyaluronic acid
• Interstitial matrix: space between cells
o Fibrillar and nonfibrillar collagen, elastin, fibronectin, proteoglycans, hyaluronate, others.
• Basement Membrane: structure that separates epithelial cells from mesenchymal cells
o Type IV collagen, laminin, heparin sulfate, proteoglycans, other glycoproteins

37
Q

Describe the function of each discussed collagen types

A

o Type I: most common form; in bone, tendons, mature scars
o Type II: articular and hyaline cartilage
o Type III: embryonic collagen, first collagen deposited in wound healing and is eventually replaced by Type I
o Type IV: NON-fibrillar; in basement membranes

38
Q

Describe the formation of collagen

A

• Triple helix of 3 polypeptide chains
o Modified
• Hydroxylation on proline and lysine residues
• Glycosylation on lysine residues
o Secreted
o Procollagen is cleaved into active form
o Cross-linked into fibrils
• Via oxidation of lysine and hydroxylysine residues
• Requires Vitamin C
• Provides tensile strength

39
Q

Elastic Fibers in wound healing

A

o Structure: elastin core surrounded by fibrillin
o Function: allows recoil after stretching
o Located: arteries, skin, uterus, lung
o Marfan Syndrome: from inherited defects in fibillin

40
Q

Fibronectin in wound healing

A

o A secreted cell adhesion protein
o Location
• Plasma: stabilizes early clot (fibrin plug)
• Cellular: secreted from fibroblasts, macrophages, endothelial cells
o Function: binds numerous molecules of ECM and integrin
• Adds structural integrity to clot
• Chemotactic for many cells
• Substrate for cellular adhesion (RGD domain)
• Substrate for other ECM protein attachment and assembly
o First ECM deposited during wound healing

41
Q

Laminin in wound healing

A

o A secreted cell adhesion protein
o Located primarily in basement membrane
o Forms tight network with Type IV collagen to maintain BM integrity
o Functions: similar to fibronectin
• Substrate for ECM protein binding (heparin, collagen)
• Substrate for cell adhesion

42
Q

Integrin in wound healing

A

o A cell surface-bound cell adhesion protein
o Transmembrane receptors
o Functions:
• Facilitate cell-cell interactions
• Facilitates cell interaction with ECM
• Binds collagen, fibronectin, laminin
• Links cell surface to cytoskeleton
• Conformation changes in cytoskeleton can initiate signal transduction → cell proliferation, apoptosis, differentiation

43
Q

Cadherin in wound healing

A

o A calcium-dependent cell surface-bound cell adhesion protein
o Functions:
• Facilitate cell-cell interactions between similar cells types
• Facilitate formation of cell junctions (zonula adherens, desmosomes)
• Linked to actin cytoskeleton via catenins to regulate cell motility, proliferation, and differentiation

44
Q

Proteoglycans in wound healing

A

o Structure: repeating disaccharide polymers bound to protein core
• Chondroitin sulfate, heparin sulfate, dermatan sulfate
o Function: forms ECM scaffold for structure and permeability

45
Q

Hyaluronic Acid in wound healing

A

o Structure: huge molecule of long repeating polysaccharides WITHOUT protein core
• Can bind lots of water
• Forms viscous, hydrated gel
o Function: allows ECM to resist compressive forces
o Deposited early in wound healing
• Facilitates cell migration and proliferation

46
Q

Explain the two mechanisms by which angiogenesis can occur

A
**• From pre-existing vessels**
 o Nitric Oxide and VEGF cause vasodilation and increased permeability
 o Metalloproteinases degrade vessel’s BM and plasmingogen activator disrupts cell-cell contact between endothelial cells
 o Endothelial cells migrate toward angiogenic activator
 o Endothelial cells proliferate
 o Endothelial cells mature and from capillary tubes
 o Periendothelial (pericytes and smooth muscle cells) cells are recruited to form mature vessels
 • **From endothelial precursor cells derived from the bone marrow**
 o Hemangioblast cells can differentiate into hematopoietic cells and vascular cells
 o Recruited into injured tissues to initiate angiogenesis
 o Unknown mechanism
47
Q

List the phases in wound healing

A
  • hemostasis phase
  • inflammatory
  • proliferative
  • maturation
48
Q

Describe the Hemostasis Phase in wound healing

A

o Function: stops the bleeding and facilitates inflammation
o Platelets activated by exposed collagen
• Aggregate
• Secrete cytokines to activate clotting and complement cascades (serotonin, bradykinin, prostaglandins, prostacyclins, thromboxane, histamine)
• Release thromboxame: transient vasoconstriction and platelet aggregation (10 minutes long)
• Factors like histamine then cause vasodilation and increased permeability for edema (entrance of water) and inflammatory cells to enter
o Plasma fibronectin/fibrin forms plug at injury site
• Early structural support

49
Q

Describe the Inflammatory phase in wound healing

A

o Function: Stop infection, clear debris, induce repair
o Early phase:
• Neutrophils appear within hours
• Attracted by chemokines (fibronectin, PDGF, TGF-b, C5b, TNF)
• Phagocytose debris and pathogens
• Secrete proteases to break down wound site
• Macrophages become predominant cell after 2 days
• Secrete growth factors, cytokines, proteases
• Phagocytose debris and pathogens
o Late phase
• Macrophage secretion peaks on days 3-4
• Secreted factors attract and activate multiple cell types needed for the proliferative phase
• Neutrophil/macrophage numbers begin to decline
• Fibroblasts become predominant cell
• Early wound ECM: fibrin, fibronectin, hyaluronic acid, adhesion glycoproteins
• Serves as anchor for cell adhesion and collagen deposition

50
Q

List the steps in the proliferative phase

A
  • Angiogenesis
  • Formation of granulation tissue
  • Fibroplasia (collagen deposition)
  • Parenchymal cell migration/proliferation (epithelialization)
  • Wound contraction
51
Q

Describe the angiogenesis of the proliferative phase

A

o Purpose: to restore perfusion to wound
o VEGF
• Increased vascular permeability
• Endothelial cell migration
• Promotes angiogenesis
o Fibrin/Fibronectin deposition in ECM facilitates endothelial cell migration
• Proteases degrade existing ECM for endothelial migration
o New thin walled vessels in wound site (granulation tissue)
• Most vessels regress via apoptosis when no longer needed

52
Q

Describe granulation tissue formation in the proliferative phase

A

o Purpose: fills defect left by injury prior to collagen deposition (fibrosis)
o 2-5 days after injury
o Composed of highly vascular loose fibrous tissue
• Scattered inflammatory cells and proliferating fibroblasts
o ECM composed of
• Fibronectin (adherence)
• Type III collagen
• Hyaluronic acid (binds water)
o Growth factors
• PDGF and TGF-beta: facilitate fibroblast migration and proliferation

53
Q

Describe fibroplasia in the proliferative phase

A

o Purpose: influx and proliferation of fibroblasts with subsequent collagen deposition
o Fibroblasts attracted and activated by TGF-b, PDGF, EGF, FGF, and cytokines
• Secreted from platelets, inflammatory cells, endothelial cells
o TGF-b is a critical mediator of fibrogenesis
• Increases fibroblast proliferation and migration
• Increases collagen and fibronectin synthesis
• Decreases ECM degradation by metalloproteinases
• Chemotactic for monocytes
o Ends 2-4 weeks after injury
• When collagen degradation > deposition

54
Q

Describe epithelialization in the proliferative phase

A

o Purpose: restores injured epithelium
o 2-3 days after injury
o Basal keratinocytes (in skin wounds)
• Proliferate from edges of wound and migrate until contact inhibition
• Migrate over granulation tissue, but under scab
• Proliferation and migration stimulated by EGF, KGF, FGF
• Migration facilitated by interaction with fibronectin/fibrin in provisional ECM of granulation tissue
• Secrete:
• Plasminogen activator
o Activates plasmin to degrade fibrin to dissolve scab
• Matrix metalloproteases
o Dissolve damaged ECM and old BM
• Growth factors and new BM
o Includes laminin and Type IV collagen

55
Q

Describe wound contraction in the proliferative phase

A

o Pulls edges of wound together to reduce wound surface area by 40-80%
o Mediated by myofibroblasts
• TGF-b induces differentiation of fibroblasts to myofibroblasts
• Myofibroblasts contain actin filaments linked to ECM
• Facilitate contraction
• As contract, fibroblasts lay down new collagen

56
Q

Describe the maturation phase

A

o Remodeling of ECM with mature scar to increase tensile strength
o Process can last over 1 year
o Collagen production = degradation
o Matrix metalloproteases degrade collagen and ECM
o Replace Type III collagen with Type I
• Collagen is organized, cross-linked, and aligned along tension lines
• Final wound strength = 80% of normal
o Replace hyaluronic acid with proteoglycans
• Heparin sulfate, chondroitin sulfate
o Decreased number of blood vessels, fibroblasts
o Mature scar: dense Type I collagen, elastic fibers, proteoglycans, scattered fibroblasts

57
Q

Describe the processes of liver regeneration and liver fibrosis following injury

A

• Regeneration
o Following a partial hepatectomy
o Compensatory growth: hepatocytes re-enter cell cycle and replicate once or twice
o Return to quiescent state
o Nonparenchymal cells also replicate (Kupffer cells, endothelial cells, stellate cells)
o Mediated by cytokines: TNF, IL-6; and growth factors: HGF, TGF-a
o No fibrosis occurs
Liver fibrosis
o With more chronic forms of injury
• Chronic viral hepatitis, alcohol abuse
o Repeated cell injury, inflammation, repair → fibrosis
o Can result in cirrhosis

58
Q

Define each type of skin wound: abrasion, laceration, incision, avulsion, amputation, and puncture

A
  • Abrasion: superficial injury from contact between skin and parallel rough surface; scrapes off epidermis
  • Laceration: tears in tissues with jagged margins
  • Incision: division of soft parts made with a knife
  • Avulsion: tissue torn loose and left hanging by flaps
  • Amputation: portion of body is completely detached
  • Puncture: narrow object penetrates body’s tissues; entrance wound is often small so don’t know the harm done to underlying tissues and vessels
59
Q

Describe the various types of surgical wound healing

A

• Primary Closure
o Wound edges are closely connected by suture, staples, tape, etc.
Delayed primary intention/closure
o Wound is initially left open
o Closed when granulation tissue is sufficiently clean and vital
Secondary intention/ closure
o When wound is contaminated or tissue has questionable vitality
o Tissues left open to scar from bottom up
o Prevents morbidity/complications and mortality
o In secondary intention (vs primary)
• Larger tissue defects
• Larger inflammatory response
• Larger amounts of granulation tissue formed
• Greater amount of wound contraction and collagen cross-linking

60
Q

List the local factors that can disrupt (enhance or retard) normal wound healing

A

o Wound type, size, location
o Vascular supply
• Poor blood supply = slower healing
• Ischemic wounds do not heal
o Oxygen supply
• Increases O2 promotes healing
o Infection
• Delays or prevents healing
• Wounds may be edematous, red, tender, drain purulent material, febrile
o Necrosis
• Lowers pH of area, causes inflammation, prevents healing
o Foreign material
• Impair healing, increased likelihood of bacterial infection
o Movement
• Pulls wounds apart
• Increases glucocorticoid circulation, inhibiting repair
o Radiation
• Prevents cells from dividing, injures epithelial cells

61
Q

List the systemic factors that can disrupt (enhance or retard) normal wound healing.

A

o Circulatory compromise
o Nutritional status
• Malnutrition: decreased protein synthesis
• Zinc deficiency: needed for metalloprotease function
• Vitamin C deficiency: collagen synthesis (scurvy)
• Vitamin A deficiency: increased requirements in wound healing, aids in epithelialization
• Vitamin B1 (thiamine) and B2 (riboflavin) deficiencies
o Diabetes mellitus: impaired circulation
o Obesity: unclear reasons, maybe from poor circulation in fatty tissues
o Hormones: glucocorticoids impair (inhibit inflammation and collagen synthesis)
o Chemotherapy: prevents cells from dividing
o Others: age, genetic disorders, malignancy, uremia

62
Q

Explain the complications of wound healing

A

Deficient scar formation
o Can lead to dehiscence (rupture) or ulceration (can occur due to poor vascularization during healing)
• Excessive formation of repair components
o Hypertrophic scars: excessive amounts of collagen in wound leading to raised scar
o Keloids: scar grows beyond original borders and doesn’t regress; can recur after removal
o Excessive granulation tissue: can prevent re-epithelialization
o Excessive fibroblast proliferation: creates a mass lesion called a desmoid or aggressive fibromatosis
Formation of contractures
o If excessive: results in disfigurement and loss of function (permanent muscle or joint fixation)
o Especially after burns

63
Q

Explain the role of mitochondrial damage in the major mechanisms of cell damage

A
o From increased Ca2+, ROS, or oxygen deprivation
 o Creates mitochondrial permeability transition pore (channel in membrane, so destroys membrane potential)
 o Contents (cytochrome c) leak into cytoplasm, trigger apoptosis
64
Q

Explain the role of loss of Calcium homeostasis or defects in membrane permeability in the mechanism of cell damage

A

o High concentration of Ca2+
o Opens mitochondrial permeability transition pore
o Activates enzymes
o Activates caspases → apoptosis

65
Q

Explain the role of oxidative stress from free radicals in the mechanism of cell damage

A

o Sources:
• Mitochondrial oxidative phosphorylation
• Radiant energy
• Leukocytes in inflammatory response
• Metals (Fe, Cu)
• Nitric oxide
o Results:
• Lipid peroxidation in membranes
• Chain reaction
• Oxidative modification of proteins
• Lesions in DNA
o Removed by:
• Antioxidants
• Transport proteins for reactive metals
• Enzymes (superoxide dismutase, catalase, glutathione peroxidase)

66
Q

Explain the role of oxidative stress from free radicals in the mechanism of cell damage

A

o Oxidative damage
o Decreased phospholipid synthesis from low ATP
o Increased phospholipid breakdown from Ca2+ activation of phospholipases
• Breakdown products also cause detergent action
o Damage to cytoskeleton scaffolding
o Results
• Loss of membrane potentials, osmotic balance
• Leakage of cell and lysosome contents
• Damage to DNA and proteins

67
Q
A

Neutrophil

Polymorphonuclear leukocyte

68
Q
A

Lymphocyte

69
Q
A

Monocyte (circulating)

Macrophage (in tissues)

70
Q
A

Eosinophil

71
Q
A

Basophil

Mast Cells (in tissues)

72
Q

Describe the vascular changes that occur with inflammation

A

• Changes in vascular flow and caliber
o Dilation of capillary bed’s pre-arterioles and post-venules
o Results in stasis (expansion of capillary bed) so sluggish blood flow
• Increased vascular permeability:
o Endothelial gaps in venules
• From vasoactive mediators (histamine, bradykinin, substance P) and cytokines (IL-1, TNF, IFN-y) causing cell constriction
o Endothelial cell injury
• Toxins, burns, chemicals → immediate sustained response, or delayed prolonged leakage
• Leukocytes
o Increased transcytosis
• VEGF induces leakage of fluid and cells via “vesiculovacuolar organelle”
o Leakage from new blood vessels
• Because leaky until maturity
• Endothelial cells are more sensitive to vasoactive mediators

End Result: edema, erythema

73
Q

List the steps involved in leukocyte recruitment and activation

A
  • Stasis
  • Margination
  • Adherence
  • Transmigration/Diapedesis
  • Migration
  • Chemotaxis
  • Leukocyte activation
  • Phagocytosis
  • Release of Leukocyte products
74
Q

Leukocyte chemotaxis in inflammation

A

WBCs move along chemical gradient
o Agents:
• Exogenous agents: bacterial products
• Endogenous agents: complement products (C5a), lipoxygenase pathway products (LTB4), cytokines (IL-8)
o Agents bind G-protein coupled receptors on WBC membrane
o Activation → stimulates polymerization of actin filaments and extension of filopodia at leading edge of WBC

75
Q

Leukocyte Phagoccytosis

A

• Recognition and attachment
o Macrophage mannose receptor recognizes mannose and fucose residues from glycoproteins and glycolipids on microbial cell walls
o Enhanced recognition and attachment if foreign object is opsonized by IgG or C3b or plasma lectins
• Engulfment
o Cytoplasm wraps around foreign material
o Forms phagosome
o Fuses with lysosome
o Lysosomal enzymes mix with phagosome contents
• Killing and degradation
o Oxygen-dependent mechanisms
• Reactive Oxygen Intermediates (ROI)
• While oxidizing NADPH, reduce oxygen to superoxide anion → hydrogen peroxide → hydroxyl radical
• Myeloperoxidase converts hydrogen peroxide → hypochlorite
• Hypochlorite destroys microbes by halogenation or lipid peroxidation
o Oxygen-Independent mechanisms
• Substances in leukocyte granules: lysozyme, lactoferrin, major basic protein, defensins, and other enzymes
o After organism is killed, pH in phagolysosome decreases
• Acid hydrolases degrade dead microbes

76
Q

Describe the factors involved in Leukocyte margination, adherence, and diapedesis

A

• E-selectin
o Expressed on cell surface of endothelial cells when cytokines present
o Bind to Sialyl-Lewis X–modified glycoprotein on leukocytes
o Weak binding, but slows down WBCs = margination
• ICAM-1 and VCAM-1
o Types of integrin ligands
o Expressed on cell surface of endothelial cells when cytokines present
o Bind to integrins on leukocytes (induced to high-affinity state from proteoglycans stimulated by chemokines)
o Strong bond, fixes leukocyte to endothelium = adherence
• PECAM-1 (CD31)
o An integrin ligand on endothelial cell surface
o Mediates diapedesis

77
Q

List four powerful chemoattractants for leukocytes

A
  • Bacterial products (LFB)
  • Complement products (C5a)
  • Products of lipoxygenase pathway (LTB4)
  • Cytokines (IL-8)
78
Q

Describe the functional effects of leukocyte activation

A
  • Modulation of leukocyte adhesion molecules
  • Phagocytosis
  • Degranulation of phagocytes and platelets
  • Secretion of cytokines (to amplify and regulate inflammation)
  • Production of arachidonic acid metabolites
  • Aggregation of platelets
79
Q

Compare emigration, chemotaxis, and phagocytosis in terms of function and sequence in acute inflammation

A
  • Emigration: to extravascular space
  • Chemotaxis: leukocyte movement along chemical gradient
  • Phagocytosis: elimination of injurious agent by WBCs
80
Q

List the chemical products involved in killing during phagocytosis

A

o Oxygen-dependent mechanisms
• Reactive Oxygen Intermediates (ROI)
• While oxidizing NADPH, reduce oxygen to superoxide anion → hydrogen peroxide → hydroxyl radical
• Myeloperoxidase converts hydrogen peroxide → hypochlorite
• Hypochlorite destroys microbes by halogenation or lipid peroxidation
o Oxygen-Independent mechanisms
• Substances in leukocyte granules: lysozyme, lactoferrin, major basic protein, defensins, and other enzymes

o After organism is killed, pH in phagolysosome decreases
• Acid hydrolases degrade dead microbes

81
Q

Describe the causes and manifestations of each of the four diseases related to deranged leukocyte function.

A

1. Defects in Leukocyte adhesion
• genetic deficiency in leukocyte adhesion molecues (LAD types 1 & 2)
• susceptible to recurrent bacterial infections, impaired wound healing
2. Defects in phagolysosome function
Chediak-Higashi syndrome
o Autosomal recessive
o Susceptible to infection due to neutropenia, defective granulation, defects in oxygen-dependent microbicidal activity
o Causes delayed microbial killing, albinism, nerve defects, bleeding disorders
Chronic Granulomatous disease
o Defects in genes for NADPH oxidase
o Deficient oxygen-dependent microbicidal activity
o Recurrent infections
3. Bone marrow suppression
• Common cause of decreased leukocyte activity
• Primary to bone marrow diseases (myelodysplasia, leukemia)
• Secondary to tumor metastases, iatrogenic bone marrow depletion (radiation therapy, chemotherapy) or acute or chronic diseases (burns, sepsis, diabetes, malnutrition, anemia)
4. Aberrant release of leukocyte products
• Underlies many inflammatory diseases: arthritis, asthma, atherosclerosis
• Causes include:
o Regurgitation during feeding—phagolysosome opens to outside
o Frustrated phagocytosis—leukocyte attaches to immune complexes that are fixed on tissues so can’t be digested
o Cytotoxic release—leukocyte ingests substance that damages its own membrane, so becomes incontinent
o Exocytosis—lysosomal granules actively secreted to outside

82
Q

List the types of acute inflammation

A
  • serous
  • fibrinous
  • suppurative/purulent
  • pseudomembranous
  • ulcerative
  • gangrene
83
Q

Serous inflammation

A

Thin, watery fluid (transudate) at site of injury

84
Q

Fibrinous inflammation

A

o Clear fluid AND fibrinogen escape vessel
o Fibringogen polymerizes → tan-pink, stringy fibrin coat
o Characteristic inflammation of linings of body cavities (pleural, pericardial, peritoneal)

85
Q

Suppurative/Purulent inflammation

A

o Lots of pus made from neutrophils, necrotic cells, and edema fluid
o Response characteristic of “pyogenic” bacteria (staphylococcus aureus, Neisseria meningitides)
o Ex. Acute appendicitis, abscess, empyma (hollow viscus filled with pus)

86
Q

Pseudomembranous inflammation

A

o Characteristic of colonic overgrowth of C. difficle or fungi
• Secondary to broad-spectrum antibiotic use or immunosuppression
o Inflammatory cells, necrotic epithelium, fibrin, and mucus form a thick film over mucosa

87
Q

Ulcerative Inflammation

A

o Destruction of an epithelial lining due to ischemic damage or infection
o Ex. Bed sore, diabetic foot ulcer, amebiasis, H. pylori, Herpes

88
Q

Gangrene inflammation

A

o Tissue necrosis secondary to interruption of the blood supply by trauma, infection, or thrombosis
o Necrotizing bacterial infection can be superimposed
o Types:
• Dry—without superinfection
• Wet—leading to liquefactive necrosis
• Gas—due to superinfection with gas-forming organisms (clostridium perfringens)
• Necrotizing fasciitis—in deep tissues
• Fournier’s gangrene of the scrotum

89
Q

Describe the relationship between acute and chronic inflammation. Give examples of each.

A

• Injurious agent in acute inflammation persists
• Progression to chronic inflammation and acquired immune system is activated
o Via antigen presenting macrophages

• Examples of chronic inflammation:
o Autoimmune diseases
o Persistent infections: Tuberculosis, syphilis, diabetic foot ulcers, gastric or duodenal ulcers, hepatitis C virus infection
o Some malignancies
o Prolonged exposure to toxic agents (particle dusts, reactive lipids)

90
Q

Define and describe the morphologic/histologic types of chronic inflammation, and give examples of each

A

• Non-specific chronic inflammation
o Mononuclear cell infiltration: Macrophages, lymphocytes, plasma cells
o Tissue destruction
o Fibrosis
• Granulomatous inflammation
o Granuloma formation
• Collection of activated (plump) macrophages
• Surrounded by collar of lymphocytes
• Can have central necrosis (caseation)
• Can have giant cells (lots nuclei)
o Limited differential diagnosis:
• Infectious: tuberculosis, leprosy, brucellosis, cat-scratch disease, fungi
• Foreign/insoluble objects
• Sarcoidosis: don’t know cause
o Granuloma contains injurious agent so not spread elsewhere

91
Q

List the systemic effects of inflammation and the responsible cytokines

A

Fever
o Pyrogens (bacterial products, IL-1, TNF) → prostaglandin synthesis in hypothalamus → reset temperature
**• Acute phase proteins: **made in liver in response to IL-6 from macrophages
o C-reactive protein: marker for acute MI
o Fibrinogen: makes erythrocytes sticky and form stacks (basis of ESR test)
o Serum amyloid protein: brings HDL to macrophages for metabolism; shows elevated macrophage activity when elevated
• Leukocytosis (elevated WBC)
o Accelerated release of WBC from bone marrow
o Increased immature forms of WBC in circulating blood (“left shift”)
o Mediated by IL-1, TNF-a from macrophages
Leukopenia: in some viral infections, malnourishment, chronic debilitation
Acute Phase Reaction: increased pulse, BP, sweating, rigors, chills, anorexia, somnolence, malaise
Sepsis (TNF, IL-1)
o Tachycardia, fever or hypothermia, hyperventilation, leukocytosis or leukopenia

92
Q

Discuss the causes and symptoms of sepsis

A

• From overwhelming bacterial infection or bacterial toxins in blood
• Mediated by TNF, IL-1
• Tachycardia
• Fever or hypothermia
• Hyperventilation
• Leukocytosis or leukopenia
• Disseminated intravascular coagulation (DIC)
o LPS and TNF induce tissue factor expression
o Induces coagulation
• Hypoglycemia: liver can’t maintain glucose levels
• Cardiovascular failure (decreased perfusion pressure)

93
Q

Compare and contrast resolution and scar

A

• Resolution
o Inflammation mediators have a short half live
o Released in rapid bursts
o Released only as stimulus persists
o Produce their own stop signals or anti-inflammatory cytokines and lipoxins
o If persists→ chronic inflammation
• Scar formation
o Removal of injurious agent
o Damaged tissue is replaced with fibrous tissue
• When extensive injury
• When involves cells with limited regenerative capacity

94
Q

Describe the role played by the kinin system in inflammation

A

• Factor XII/Hageman Factor activated by exposed collagen, BM, activated platelets
• It then activates precursor prekallikrein to kallikrein
• Converts high molecular weight kininogen (HMWK) to Bradykinin
o Effects: pain, increased vascular permeability
o Rapidly cleared by kininases (Ex. ACE in lungs)

95
Q

Describe the role played by vasoactive amines in inflammation

A

• Histamine
o Mast cells, basophils, platelets
o Dilation of arterioles, increased venule permeability
o Principle mediator of immediate transient response
• Serotonin
o Platelets and enterochromaffin cells
o Released when platelets aggregate
o Causes increased vessel permeability

96
Q

Describe the role played by the complement system in inflammation

A

• Produced by liver, circulate in plasma in inactive configuration
• Activation cascade
• Activated by:
o Classical pathway
• Antigen-antibody complexes bind to complement protein C1
• Initiates cascade
o Alternative pathway
• Direct activation of complement protein C3 from microbial surface molecules or Factor XII
o Lectin Pathway
• C1 activated by serum lectin bound to mannose on bacteria surface
Common part in pathways: C3 cleavage and activation
Effector complement proteins:
o C5a: chemotactic agent, attracts leukocytes, activates arachidonic acid metabolism
o C3a and C5a: anaphylatoxins (release and cause vascular dilation)
o C3b: an opsonin, targets bacteria for phagocytosis
o Membrane Attack Complex (MAC): from aggregation of proteins C5-C9, create holes in microbe membrane to lyse
• Regulation
o Complement control proteins acting on convertases
o Inhibitors of complement in serum, also protect self-cells
o C1 inhibitor: circulating serine protease that irreversibly binds to activated C1

97
Q

Describe the role played by arachidonic acid metabolites in inflammation

A
  • Made from cell membrane in response to external stimuli
  • Bind to G-protein couples receptors

• Mediate inflammatory processes:
o Vasodilation/constriction
o Platelet aggregation
o Leukocyte adhesion and chemotaxis

• Eicosanoid production pathway:
o Cyclooxygenase pathway → prostaglandins and thromboxane
o Lipoxygenase pathway → leukotrienes and lipoxins
• Blocked or inhibited by drugs: steroids, aspirin, NSAIDS, COX-2 inhibitors

98
Q

Describe the role played by the clotting system in inflammation

A

• Initiated by Factor XII (kinin system): activated by collagen, BM, activated platelets
• Produces Thrombin
o Links clotting cascade to inflammation
• Binds G-protein coupled receptors
• Activates platelets, endothelial cells, smooth muscle cells
Causes:
• Mobilization of selectins
• Change in endothelial cell shape
• Chemokine production
• Induction of arachidonic acid pathway
• Production of PAF and NO
o Regulation
• Enzymes inhibited by antithrombins, proteins C and S, tissue factor pathway inhibitor (TFPI)
o Fibrinolytic System
• Antagonizes clotting cascade
• Tissue plasminogen activator cleaves plasminogen → plasmin
• Plasmin cleaves fibrin → fibrin split products
• Plasmin cleaves C3 → C3a (increased vascular permeability)
• Plasmin can activate Factor XII

99
Q

Describe the role played by cytokines in inflammation

A
  • Protein that modulates function of other cell types
  • In inflammation: TNF-1, IL-1
100
Q

State how the complement, coagulation and kinin systems interact

A

• Kallikrein directly activates C5 to C5a
• Plasmin can directly activate C3
• Complement cascade can activate C5 and C3
• Factor XII activates clotting cascade, kinin system, fibrinolytic system, complement system
• Factor XII and Kallikrein are autocatalytic amplifiers
o Can activate each other
• Bradykinin, C3a, C5a, and thrombin are all inflammation mediators

101
Q

Describe the effect of steroids, NSAIDs, aspirin and other anti-inflammatory drugs on arachidonic acid metabolism

A

• Steroids
o Inhibit phospholipases
o Arachidonic acid not available to make eicosanoids
NSAIDs, acetaminophen, aspirin, COX inhibitors
o Inhibit cyclooxygenase pathway
o Blocks prostaglandin, prostacyclin, and thromboxane synthesis

102
Q

Discuss the role of free radicals in inflammation.

A

• Produced by leukocytes when microbes, chemokines or immune complexes
• Products of NADPH oxidative system:
o Superoxide anion, hydrogen peroxide, hydroxyl radical
o Reactive nitrogen intermediates when combined with NO
• Effects
o Destroy phagocytosed microbes
o Extracellular release potentiates inflammatory response
• Increased chemokines, cytokines, endothelial leukocyte adhesion
o Damaging if extracellular release
• Injure endothelial cells, parenchymal cells, RBCs
• Inactivate antiproteases in extracellular tissues
o Counteracted by antioxidants
• Ceruloplasmin, transferrin, superoxide dismutase, glutathione peroxidase, catalase

103
Q

Platelet Activating Factor (PAF)

A

• Derived from phospholipids
• Produced by platelets, basophils/mast cells, neutrophils, monocytes/macrophages, endothelial cells
• Specific G-protein coupled receptor on effector cells
• Effects
o Platelet aggregation
o Vasodilation (more potent than histamine)
o Constriction of non-vascular smooth muscles
o Increased leukocyte adhesion
o Chemotaxis
o Degranulation
o Oxidative burst
o Potentiation of arachidonic acid metabolism
****elicits most of cardinal features of inflammation *

104
Q

Nitric Oxide

A

• Gaseous signaling molecule
• 3 different nitric oxide synthetase enzymes:
1)phagocytes
• produces NO as free radical
• causes injury to bacteria and parasites
2) endothelial cells
• NO produced causes vasodilation by smooth muscle relaxation
3) Brain

• Produced when increased cytosolic calcium or cytokine stimulation of macrophages
• Effects
o Paracrine inflammation inhibitor
• Reduces platelet aggregation
• Reduces leukocyte recruitment
o Vasodilator
o Microbicidal (via reactive nitrogen intermediates)
• Short half life
• Involved in diseases
o Atherosclerosis, hypertension, diabetes

105
Q

Substance P

A
  • Pro-inflammatory neuropepetide
  • Released in response to psychological stress
  • Linked to systemic stress response mediated by CRF
  • Activate mast cells and leukocytes
  • Involved in some poorly understood inflammatory conditions: Asthma, eczema, migraine, fibromyalgia, rosacea, psoriasis
106
Q

Anaphylaxis

A

• Type I hypersensitivity allergic reaction
• Cross-linking of IgE receptors on mast cells
• Degranulation of mast cells
• Histamine release
o Vasodilation → rash, redness, edema
o Bronchoconstriction → respiratory distress
• Medical emergency
o Administer epinephrine (bronchodilation, regulate heart beat)

107
Q

Complement deficiency

A

• C3 deficiency
o Increases susceptibility to infection
• Defective MAC formation
o Unable to clear infection by Neisseria

108
Q

Paroxysmal nocturnal hemoglobinuria

A
  • Complement Inhibitor deficiency
  • Mutation in gene controlling complement activation
  • Recurrent complement-mediated intravascular hemolysis
  • Chronic hemolytic anemia
109
Q

Alpha-1 antitrypsin deficiency

A

• Alpha-1 antitrypsin is an antiprotease
o Major inhibitor of neutrophil elastase and other proteases
• Sustained action of elastases cause digestion of extracellular tissues
• Autosomal recessive
o Mutation in protease inhibitor gene
• Pathologic effects
o Panacinar pulmonary emphysema
o Cholestatic hepatitis leading to cirrhosis
o Variable expression throughout life

110
Q

Discuss how chemical mediators of inflammation might be developed for therapy.
Give examples of their current therapeutic use

A

• Disrupt inflammatory processes in disease
o Allergy, autoimmune, transplant, malignancy
Block histamine in allergic diseases
o Block release (cromolyn sodium)
o Block histamine receptor (loratadine)
Block arachidonic acid metabolism
o Steroids →autoimmune diseases, transplants, allergy
o Aspirin and NSAIDs →arthritis, etc.
o COX-2 inhibitors (Vioxx, Celebrex, Bextra) → arthritis
Block effect of TNF
o Autoimmune diseases → Crohn’s, rheumatoid arthritis
• Block effect of IL-1
o Clinical trials to treat rheumatoid arthritis