CHAPTER 2
Inflammation
(5 OBJECTIVES)
1) (Concept) Understand the chain,
progression, or sequence of
vascular and cellular...
2) (Rote?) Learn the roles of various
“chemical mediators” of acute
inflammation
3) Know the three possible outcomes of
ac...
SEQUENCE OF EVENTS
•
•
•
•
•
•
•
•
•

NORMAL HISTOLOGY 
VASODILATATION 
INCREASED VASCULAR PERMEABILITY 
LEAKAGE OF EXU...
ACUTE INFLAMMATION
• “PROTECTIVE”
RESPONSE

•NON-specific
ACUTE INFLAMMATION
• VASCULAR EVENTS
• CELLULAR EVENTS (PMN or
PolyMorphonuclear Neutrophil,
Leukocyte?, “POLY”, Neutrophi...
ACUTE
INFLAMMATION
Neutrophil

Polymorphonuclear
Leukocyte, PMN, PML
“Leukocyte”
Granulocyte, Neutrophilic
granulocyte
“Po...
HISTORICAL
HIGHLIGHTS
(Egypt, 3000 BC)

Rubor
Calor
Tumor
Dolor
5th (functio laesa)
STIMULI
for acute inflammation
• INFECTIOUS
• PHYSICAL
• CHEMICAL
• Tissue Necrosis
• Foreign Bodies (FBs)
• Immune “respo...
Vascular Changes
• Changes in Vascular Flow
and Caliber
• Increased Vascular
Permeability
INCREASED PERMEABILITY

• DILATATION
• Endothelial “gaps”
• Direct Injury
• Leukocyte Injury
• Transocytosis (endo/exo)
• ...
LEAKAGE OF
PROTEINACEOUS FLUID
(

EXUDATE, NOT
TRANSUDATE)
EXTRAVASATION of
PMNs

• MARGINATION
(PMN’s go toward
wall)
• ROLLING (tumbling
and HEAPING)
• ADHESION
• TRANSMIGRATION
(...
ADHESION MOLECULES
(glycoproteins) affecting
ADHESION and TRANSMIGRATION

• SECRETINS (from
endothelial cells)
• INTEGRINS...
CHEMOTAXIS
PMNs going to the site of “injury”
AFTER transmigration
LEUKOCYTE
“ACTIVATION”
• “triggered” by the offending stimuli for PMNs to:
– 1) Produce eicosanoids (arachidonic acid
deri...
PHAGOCYTOSIS
• RECOGNITION
• ENGULFMENT
• KILLING
(DEGRADATION/
DIGESTION)
CHEMICAL MEDIATORS
• From plasma or cells
• Have “triggering” stimuli
• Usually have specific
targets
• Can cause a “casca...
CLASSIC MEDIATORS
•
•
•
•
•

HISTAMINE
SEROTONIN
COMPLEMENT
KININS
CLOTTING
FACTORS
• EICOSANOIDS
• NITRIC OXIDE

• PLATEL...
HISTAMINE
• Mast Cells,
basophils
• POWERFUL
Vasodilator
• Vasoactive
“amine”
• IgE on mast
cell
SEROTONIN
• (5HT,

5-Hydroxy-

Tryptamine)
• Platelets and
EnteroChromaffin Cells
• Also vasodilatation, but
more indirect...
COMPLEMENT SYSTEM
• >20
components,
in circulating
plasma
• Multiple sites
of action, but
LYSIS is the
underlying
theme
KININ SYSTEM
• BRADYKININ is KEY component, 9 aa’s
• ALSO from circulating plasma
• ACTIONS
– Increased permeability
– Smo...
CLOTTING
FACTORS
• Also from circulating plasma
• Coagulation, i.e., production of
fibrin
• Fibrinolysis
EICOSANOIDS
(ARACHIDONIC ACID DERIVATIVES)

• Part of cell membranes
• 1) Prostaglandins (incl.
Thromboxanes)
• 2) Leukotr...
Prostaglandins
(thromboxanes included)
• Pain
• Fever
• Clotting
Leukotrienes
• Chemotaxis
• Vasoconstriction
• Increased Permeability
Lipoxins
• INHIBIT chemotaxis
• Vasodilatation
• Counteract actions of
leukotrienes
Platelet-Activating Factor
(PAF)
• Phospholipid
• From MANY cells,
like eicosanoids
• ACTIVATE
PLATELETS,
powerfully
CYTOKINES/CHEMOKINES
• CYTOKINES are PROTEINS produced by
MANY cells, but usually LYMPHOCYTES
and MACROPHAGES, numerous ro...
NITRIC OXIDE
• Potent vasodilator
• Produced from the action
of nitric oxide synthetase
from arginine
LYSOSOMAL CONSTITUENTS

• PRIMARY

• SECONDARY

• Also called
AZUROPHILIC, or
NON-specific

• Also called SPECIFIC

• Myel...
FREE RADICALS
• O2 – (SUPEROXIDE)

• H2O2 (PEROXIDE)
• OH- (HYDROXYL RADICAL)

•

VERY VERY DESTRUCTIVE
NEUROPEPTIDES
• Produced in CNS (neurons)
• SUBSTANCE P
• NEUROKININ A
OUTCOMES OF
ACUTE INFLAMMATION
• 1) 100% complete
RESOLUTION
• 2) SCAR
• 3)CHRONIC inflammation
Morphologic PATTERNS
of Acute INFLAMMATION
(EXUDATE)
• Serous (watery)

• Fibrinous (hemorrhagic,
rich in FIBRIN)

• Suppu...
BLISTER, “Watery”, i.e., SEROUS
FIBRINOUS
PUS
=
PURULENT

ABSCESS
=
POCKET
OF
PUS
=
NEUTROPHILS
PURULENT, FIBRINOPURULENT
ULCERATIVE
SEQUENCE OF EVENTS
•
•
•
•
•
•
•
•
•

NORMAL HISTOLOGY 
VASODILATATION 
INCREASED VASCULAR PERMEABILITY 
LEAKAGE OF EXU...
CHRONIC INFLAMMATION

(MONOS)

“MONO”CYTE

LYMPHOCYTE

MACROPHAGE
HISTIOCYTE
APC
CAUSES of
CHRONIC INFLAMMATION
• 1) PERSISTENCE of
Infection
• 2) PROLONGED
EXPOSURE to insult
• 3) AUTO-IMMUNITY
Cellular Players
• LYMPHOCYTES
• MACROPHAGES
(aka, HISTIOCYTES)
• PLASMA CELLS
• EOSINOPHILS
• MAST CELLS
MORPHOLOGY
• INFILTRATION
• TISSUE DESTRUCTION
• HEALING
GRANULOMAS
GRANULOMATOUS INFLAMMATION
4 COMPONENTS

FIBROBLASTS

LYMPHS

HISTIOS
“GIANT” CELLS
GRANULOMAS
GRANULOMATOUS INFLAMMATION

CASEATING (TB)
NON-CASEATING
LYMPHATIC
DRAINAGE
• SITE REGIONAL LYMPH NODES
SYSTEMIC MANIFESTATIONS
(NON-SPECIFIC)

• FEVER, CHILLS

• C-Reactive Protein (CRP)

• “Acute Phase” Reactants, i.e., α1-α...
NORMAL SPE

Serum
Protein
Electrophoresis

In ACUTE
Inflammation
Alpha-1 & alpha-2
are increased, i.e.,
“acute phase”
reac...
Minarcik robbins 2013_ch2-inflam
Minarcik robbins 2013_ch2-inflam
Minarcik robbins 2013_ch2-inflam
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  • Think of it as a Cecil B. DeMille epic movie!
  • Who was Cecil B. DeMille?
  • The sequence of changes occurring in acute inflammation are NOT specific for the stimuli which cause them
  • These are the three “phases”, in order, of acute inflammation. Please NOTE they, in no way, are the independent of each other, and as you might suspect by now, quite the contrary, CRUCIALLY all wrapped up with each other!
  • Many names, same cell
  • The four “cardinal”, i.e., “classic” signs of inflammation, translated, literally, 1) redness, 2) heat, 3) swelling, 4) pain.
    Just like a fith Marx bother, Gummo, was often added, so was the term “functio laesa” or “loss of function”
  • The usual suspects, again. “Stimuli”, like “etiologic agents” is a very elusive term if you like to think in terms of ultimate causes.
  • Vascular changes occur BEFORE any infiltration of inflammatory cells arrive.
  • These are all events which either cause, or result, from the phenomenon of “increased permeability”
  • Transudate vs. Exudate. Transudates can be thought of as being fairly pure water. Transudates are water PLUS most serum proteins, fibrin, and many blood cells often. So which one do you think requires bigger holes in the endothelium, transudates or exudates?
  • The four things neutrophils do, in order, in acute inflammation. This is beautifully demonstrated in live cell imaging!
  • Secretins and integrins are classes of substances to help neutrophils stick to vessel walls and migrate through the wall. Yes they are CAMs.
  • CHEMOkines induce CHEMO-taxis, that why their called CHEMO-kines.
  • These three events are the results of leukocytes (i.e., neutrophils) being “activated”
  • The three phases of phagocytosis, in correct order. 1) Recognition2) Engulfment3) Digestion (cell probably already dead)
  • These are the common features of ALL “chemical mediators” in acute inflammation. This is the shovelling part!
  • How many of the 4 cardinal signs of inflammation can histamine cause, by virtue of its being a powerful vasodilator? 3-4?
  • Serotonin is widely and primarily thought as being a neurotransmitter involved in the full spectrum of emotional responses, but its role in acute inflammation is just as powerful.
  • Complement fixation is the end stage of a cascade of multiple chemical events, similar to coagulation, which ultimately result in lysis of cell membranes, hopefully, membranes of bad cells.
  • Bradykinin is a potent endothelium-dependent vasodilator, causes contraction of non-vascular smooth muscle, increases vascular permeability and also is involved in the mechanism of pain.
  • Coagulation is also a cascade, like complement fixation.
  • Three classic eicosanoids, new classes are also being discovered. ALL are derivatives from arachidonic acid. Eicosanoids can also be directly attributed to causing the 4 cardinal signs of inflammation. http://en.wikipedia.org/wiki/Eicosanoid
    The problem with Eicosanoids is that you NEVER get the BIG picture: Here’s the BIG PICTURE NOW!
  • Arachidonic acid
  • When you think of the three main things that ASPIRIN does, you can remember the three main properties of the prostaglandins.
  • Click back to the previous slide on LEOKITRIENES and realize that LIPOXINS generally do the OPPOSITE of what LEUKOTRIENES do.
  • It is produced in response to specific stimuli by a variety of cell types, including neutrophils, basophils, platelets, and endothelial cells. From wiki:Platelet-activating factor, also known as a PAF, PAF-acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine) is a potentphospholipid activator and mediator of many leukocyte functions, including platelet aggregation and degranulation, inflammation, and anaphylaxis. It is also involved in changes to vascular permeability, the oxidative burst, chemotaxis of leukocytes, as well as augmentation of arachidonic acid metabolism in phagocytes.
  • There are gazillions of cytokines/chemokines. The two most classical and famous ones are TNF-alpha and Interleukin-1.
    TNF-alpha, also called tumor necrosis factor, or cachectin, is a substance that is destructive of human tissues, and is a key player in “cachexia”.
    Interleukin-1 was the first of many interleukins discovered and generally propagates the inflammatory response at many levels and also has a significant effect on T-cells.
  • Which drug INCREASES the effect of nitric oxide? Hint: you get spam ads for it 10 times a day in your spam, even if you are a female.
  • MPO produces hypochlorous acid and tyrosyl radical are cytotoxic, so they are used by the neutrophil to kill bacteria and other pathogens. It is what makes pus look greenish yellow.
    Lactoferrin (LF), also known as lactotransferrin (LTF), is a globular multifunctional protein with antimicrobial activity (bacteriocide, fungicide)
    Lysozymes, also known as muramidase or N-acetylmuramide glycanhydrolase, are a family of enzymes (EC 3.2.1.17) which damage bacterial cell walls by causing hydrolysis.
  • Free radical are generated through a variety of enzymatic pathways as one of the main killing mechanisms of microbes. Free radicals themselves are just as toxic to human cells as they are microbes. Ultimately, they all affect the NADPH system.
  • Substance P is an 11 amino acid polypeptide tied into many things including mood disorders, anxiety, stress, reinforcement, respiration rate, neurotoxicity, nausea, emesis, and pain. The Neurokinins are also peptide neurotransmitters involved in many things.
  • Three classic outcomes of acute inflammation
  • FOUR patterns of acute inflammation:
    (OneLook.com has 133 adjectives to the word “inflammation”)
  • FIBRIN is the endpoint of coagulation and had a characteristic appearance both grossly and microscopically. Do you remember hearing the term fibrin-OID necrosis too?
  • It is EXTREMELY important to be able to recognize neutrophils (Polys) in H&E sections. The key tip is, OFTEN, they might NOT look multilobulated at first, but upon close examination, they are!
  • ULCERS (i.e., pathologic LOSS of mucosal or epithelial coverings, are both the CAUSE as well as a RESULT of acute inflammation. WHY? Identify the FOUT layers of the colon here, mucosa, submucosa, muscularis, and finally adventitia/serosa.
  • If there was only ONE slide you needed to memorize for this chapter, THIS would be it!
  • Please understand the DIFFERENCE between a MONO-cyte, and a generic MONO-nucleated cell.
  • What does chronic inflammation look like? ANS: Infiltrates of lymphs and monos “peppering” normal histology.
    Most auto-immune inflammations are long standing, or “chronic” clinically as well.
  • Please note that the “cellular” players of chronic inflammation are NOT the baseball players who play in US Cellular Field in Chicago, i.e., the White Sox.
  • Know, ALWAYS, the FOUR cells of granulomatous inflammation, and the FOUR common types of granulomatous infections: 1) TB, 2) Sarcoid, 3) Fungi, 4) Foreign Bodies.
    Why do granulomas form, rather than just acute or chronic inflammation? Very simple, you need to bring your friends if your enemy is too big?
  • The drainage patters of acute or chronic inflammation follow the same general drainage patterns of tumor cells.
  • CRP is a member of the class of acute phase reactants as its levels rise dramatically during inflammatory processes occurring in the body. It is thought to assist in complement binding to foreign and damaged cells and affect the humoral response to disease. It is also believed to play an important role in innate immunity, as an early defense system against infections.
  • Which TWO of these 5 “hills” are significantly higher in nonspecific systemic acute inflammation?
    Answer: alpha-1 and alpha-2
  • Minarcik robbins 2013_ch2-inflam

    1. 1. CHAPTER 2 Inflammation (5 OBJECTIVES) 1) (Concept) Understand the chain, progression, or sequence of vascular and cellular events in the histologic evolution of acute inflammation
    2. 2. 2) (Rote?) Learn the roles of various “chemical mediators” of acute inflammation 3) Know the three possible outcomes of acute inflammation 4) Visualize the morphologic patterns of acute inflammation 5) Understand the causes, morphologic patterns, principle cells, minor cells, of chronic and granulomatous inflammation
    3. 3. SEQUENCE OF EVENTS • • • • • • • • • NORMAL HISTOLOGY  VASODILATATION  INCREASED VASCULAR PERMEABILITY  LEAKAGE OF EXUDATE  MARGINATION, ROLLING, ADHESION  TRANSMIGRATION (DIAPEDESIS)  CHEMOTAXIS  PMN ACTIVATION  PHAGOCYTOSIS: Recognition, Attachment, Engulfment, Killing (degradation or digestion)  • TERMINATION  • 100% RESOLUTION, SCAR, or CHRONIC INFLAMMATION are the three possible outcomes
    4. 4. ACUTE INFLAMMATION • “PROTECTIVE” RESPONSE •NON-specific
    5. 5. ACUTE INFLAMMATION • VASCULAR EVENTS • CELLULAR EVENTS (PMN or PolyMorphonuclear Neutrophil, Leukocyte?, “POLY”, Neutrophil, Granulocyte, Neutrophilic Granulocyte • “MEDIATORS”
    6. 6. ACUTE INFLAMMATION Neutrophil Polymorphonuclear Leukocyte, PMN, PML “Leukocyte” Granulocyte, Neutrophilic granulocyte “Poly-” Polymorph
    7. 7. HISTORICAL HIGHLIGHTS (Egypt, 3000 BC) Rubor Calor Tumor Dolor 5th (functio laesa)
    8. 8. STIMULI for acute inflammation • INFECTIOUS • PHYSICAL • CHEMICAL • Tissue Necrosis • Foreign Bodies (FBs) • Immune “responses”, or “complexes”
    9. 9. Vascular Changes • Changes in Vascular Flow and Caliber • Increased Vascular Permeability
    10. 10. INCREASED PERMEABILITY • DILATATION • Endothelial “gaps” • Direct Injury • Leukocyte Injury • Transocytosis (endo/exo) • New Vessels
    11. 11. LEAKAGE OF PROTEINACEOUS FLUID ( EXUDATE, NOT TRANSUDATE)
    12. 12. EXTRAVASATION of PMNs • MARGINATION (PMN’s go toward wall) • ROLLING (tumbling and HEAPING) • ADHESION • TRANSMIGRATION (DIAPEDESIS)
    13. 13. ADHESION MOLECULES (glycoproteins) affecting ADHESION and TRANSMIGRATION • SECRETINS (from endothelial cells) • INTEGRINS (from many cells)
    14. 14. CHEMOTAXIS PMNs going to the site of “injury” AFTER transmigration
    15. 15. LEUKOCYTE “ACTIVATION” • “triggered” by the offending stimuli for PMNs to: – 1) Produce eicosanoids (arachidonic acid derivatives) • Prostaglandin (and thromboxanes) • Leukotrienes • Lipoxins – 2) Undergo DEGRANULATION – 3) Secrete CYTOKINES
    16. 16. PHAGOCYTOSIS • RECOGNITION • ENGULFMENT • KILLING (DEGRADATION/ DIGESTION)
    17. 17. CHEMICAL MEDIATORS • From plasma or cells • Have “triggering” stimuli • Usually have specific targets • Can cause a “cascade” • Are short lived
    18. 18. CLASSIC MEDIATORS • • • • • HISTAMINE SEROTONIN COMPLEMENT KININS CLOTTING FACTORS • EICOSANOIDS • NITRIC OXIDE • PLATELET ACTIVATING FACTOR (PAF) • CYTOKINES • /CHEMOKINES • LYSOSOME CONSTITUENTS • FREE RADICALS • NEUROPEPTIDES
    19. 19. HISTAMINE • Mast Cells, basophils • POWERFUL Vasodilator • Vasoactive “amine” • IgE on mast cell
    20. 20. SEROTONIN • (5HT, 5-Hydroxy- Tryptamine) • Platelets and EnteroChromaffin Cells • Also vasodilatation, but more indirect • Evokes N.O. synthetase (a ligase) from argenine
    21. 21. COMPLEMENT SYSTEM • >20 components, in circulating plasma • Multiple sites of action, but LYSIS is the underlying theme
    22. 22. KININ SYSTEM • BRADYKININ is KEY component, 9 aa’s • ALSO from circulating plasma • ACTIONS – Increased permeability – Smooth muscle contraction, NON vascular – PAIN
    23. 23. CLOTTING FACTORS • Also from circulating plasma • Coagulation, i.e., production of fibrin • Fibrinolysis
    24. 24. EICOSANOIDS (ARACHIDONIC ACID DERIVATIVES) • Part of cell membranes • 1) Prostaglandins (incl. Thromboxanes) • 2) Leukotrienes • 3) Lipoxins (new) MULTIPLE ACTIONS AT MANY LEVELS
    25. 25. Prostaglandins (thromboxanes included) • Pain • Fever • Clotting
    26. 26. Leukotrienes • Chemotaxis • Vasoconstriction • Increased Permeability
    27. 27. Lipoxins • INHIBIT chemotaxis • Vasodilatation • Counteract actions of leukotrienes
    28. 28. Platelet-Activating Factor (PAF) • Phospholipid • From MANY cells, like eicosanoids • ACTIVATE PLATELETS, powerfully
    29. 29. CYTOKINES/CHEMOKINES • CYTOKINES are PROTEINS produced by MANY cells, but usually LYMPHOCYTES and MACROPHAGES, numerous roles in acute and chronic inflammation –TNFα, IL-1, by macrophages • CHEMOKINES are small proteins which are attractants for PMNs (>40), e.g., CXC, CC, CX3C, XC families, PF-4, IL-8
    30. 30. NITRIC OXIDE • Potent vasodilator • Produced from the action of nitric oxide synthetase from arginine
    31. 31. LYSOSOMAL CONSTITUENTS • PRIMARY • SECONDARY • Also called AZUROPHILIC, or NON-specific • Also called SPECIFIC • Myeloperoxidase • Lysozyme (Bact.) • Acid Hydrolases • • • • Lactoferrin Lysozyme Alkaline Phosphatase Collagenase
    32. 32. FREE RADICALS • O2 – (SUPEROXIDE) • H2O2 (PEROXIDE) • OH- (HYDROXYL RADICAL) • VERY VERY DESTRUCTIVE
    33. 33. NEUROPEPTIDES • Produced in CNS (neurons) • SUBSTANCE P • NEUROKININ A
    34. 34. OUTCOMES OF ACUTE INFLAMMATION • 1) 100% complete RESOLUTION • 2) SCAR • 3)CHRONIC inflammation
    35. 35. Morphologic PATTERNS of Acute INFLAMMATION (EXUDATE) • Serous (watery) • Fibrinous (hemorrhagic, rich in FIBRIN) • Suppurative (PUS) • Ulcerative
    36. 36. BLISTER, “Watery”, i.e., SEROUS
    37. 37. FIBRINOUS
    38. 38. PUS = PURULENT ABSCESS = POCKET OF PUS = NEUTROPHILS
    39. 39. PURULENT, FIBRINOPURULENT
    40. 40. ULCERATIVE
    41. 41. SEQUENCE OF EVENTS • • • • • • • • • NORMAL HISTOLOGY  VASODILATATION  INCREASED VASCULAR PERMEABILITY  LEAKAGE OF EXUDATE  MARGINATION, ROLLING, ADHESION  TRANSMIGRATION (DIAPEDESIS)  CHEMOTAXIS  PMN ACTIVATION  PHAGOCYTOSIS: Recognition, Attachment, Engulfment, Killing (degradation or digestion)  • TERMINATION  • 100% RESOLUTION, SCAR, or CHRONIC inflammation
    42. 42. CHRONIC INFLAMMATION (MONOS) “MONO”CYTE LYMPHOCYTE MACROPHAGE HISTIOCYTE APC
    43. 43. CAUSES of CHRONIC INFLAMMATION • 1) PERSISTENCE of Infection • 2) PROLONGED EXPOSURE to insult • 3) AUTO-IMMUNITY
    44. 44. Cellular Players • LYMPHOCYTES • MACROPHAGES (aka, HISTIOCYTES) • PLASMA CELLS • EOSINOPHILS • MAST CELLS
    45. 45. MORPHOLOGY • INFILTRATION • TISSUE DESTRUCTION • HEALING
    46. 46. GRANULOMAS GRANULOMATOUS INFLAMMATION 4 COMPONENTS FIBROBLASTS LYMPHS HISTIOS “GIANT” CELLS
    47. 47. GRANULOMAS GRANULOMATOUS INFLAMMATION CASEATING (TB) NON-CASEATING
    48. 48. LYMPHATIC DRAINAGE • SITE REGIONAL LYMPH NODES
    49. 49. SYSTEMIC MANIFESTATIONS (NON-SPECIFIC) • FEVER, CHILLS • C-Reactive Protein (CRP) • “Acute Phase” Reactants, i.e., α1-α2 • Erythrocyte Sedimentation Rate (ESR) increases • Leukocytosis • Pulse, Blood Pressure • Cytokine Effects, e.g., TNF(α), IL-1
    50. 50. NORMAL SPE Serum Protein Electrophoresis In ACUTE Inflammation Alpha-1 & alpha-2 are increased, i.e., “acute phase” reactants.
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