Lecture 142: Inflammation (Pathology)

Inflammation

response to injury of cell

• purpose: localize and eliminate cause of cell injury and to restore tissue normality
• itis

What does inflammation release?

chemical mediators
vascular changes
leukocyte changes

Acute vs chronic inflammation

Acute:

• fast
• minute-hours
• neutrophils

Chronic:

• slow, days or longer, monocytes, macrophages, lymphocytes

Cardinal signs of inflammation

Redness
warmth
swelling
pain
loss of function

Causes of inflammation

• infection
• immune reaction
• tissue necrosis
• foreign bodies
• trauma
• radiation
• burns

How does acute inflammation happen?

stimuli - vascular - cellular - phagocytosis - terminate inflammation - consequences

inflammatory response

recognition - recruitment - removal - regulation - repair

What happens if hydrostatic and oncotic pressure are not in equilibrium?

transudate: low protein - little cell material - low gravity

high hydrostatic pressure - localized edema

decreased oncotic pressure - generalized edema

Edema

excessive fluid in extravascular space

Vasodilation

trigger - histamine - relaxation of vascular smooth muscle - increase hydrostatic - transudate
increased blood flow - warm and edema

Important molecules in vasodilation

Histamine:

• stored in mast cells

NO:

• produced by endothelial cells
• signaling molecule

both relax vascular smooth muscle

Vascular permeability

leakiness of vessels affect hemodynamics

• increased permeability - exudate: high protein

Pus: inflammatory: rich in leukocytes, dead cells

Transudate vs exudate

Transudate:

• low protein, low cell content
• imbalance in hydrostatic pressure and oncotic but no change in permeability

exudate:

• high protein
• high cell content
• increased permeability
• inflammation

Mechanism of increase in vascular permeability

histamine - retraction of endothelial - openings in venules - leakage - exudate

Vascular congestion

vasodilation + permeability

• stasis: slowing of blood flow

Mechanism:

• Vasodilation- increased diameter (hemodynamics)
  • Transudation- decreased fluid higher concentration of RBCs higher viscosity of blood (leads to stasis)
  • Permeability- loss of fluid (decreased flow)

hemodynamic changes result in?

accumulate neutrophils - peripheral displacement - margination

Prostaglandins reaction

• pain, warmth, redness
• sensitize nerve endings to bradykinin (arterial vasodilation)

Histamine and NO symptoms

redness, warmth, swelling (edema)

Bradykinins:

• vasodilation in low concentrations
• vasoconstriction at high concentrations

AA metabolites

• derived from linoleic acid (fatty acid)
• prostaglandins and leukotrienes
• Prostaglandins: blocked by aspirin (COX enzymes)
• leukotrienes: vasoconstriction, permeability

Cellular responses in inflammation purpose and mediation:

Purpose: mobilize immune cells out of circulation to site of cellular injury

Mediated by adhesion molecules and cytokines

Steps to cellular inflammation

Within vessel lumen:
Margination
Rolling
Adhesion

Through lumen to site:
Transmigration
Chemotaxis

How does rolling begin?

Cytokines: signaling molecules made by cells in response to agents

• TNF and IL1:
• mediate inflammation
• produced by macrophages and lymphocytes

Chronic inflammation macrophages:

Il-12, IFN gamma, IL-17 (T lymphocytes)

Systemic effects

• Fever
• leukocytosis
• increased acute phase proteins
• decreased appetite
• increased sleep

Rolling

slow down leukocytes

• express selectins on endothelial cells

Selectins vs Neutrophils

Selectins

• low affinity adhesion on neutrophils (L) and Endothelial (E)

Neutrophils

• naturally express selectins

endothelial require stimulation to express selectins

Expression of both regulated by TNF and IL1

Adhesion:

Purpose: stop leukocytes
Mechanism:

• activity of high affinity integrins on leukocytes
  integrins stimulated by IL1 and TNF

Selectins vs integrins and chemokines

Selectins: rolling
Integrins: firm adhesion
chemokines: activate neutrophils to increase affinity of integrins

Transmigration (diapedesis)

migration of leukocytes through vessel wall
Mechanism: endothelial cells retracted, leukocytes travel between
mainly in post capillary venules

• once in endothelium, pierce basement membrane by secreting collagenases

Chemotaxis

chemotactic agents - activate GPCR - activate 2nd messengers - increase cytosolic Ca enzymes - polymerize actin + myosin for migration

Complement system

more than 20 soluble proteins

• end: lysis
• enzyme cascade where cleavage products cause increased vascular permeability, chemotaxis, opsonization

Importance of complement:

Critical step: proteolysis of C3

• all pathways lead to C3 convertase enzyme formation which splits C3 to C3A and B

C3a, C5a, C4a

stimulate histamine and cause increased vascular permeability and vasodilation

• anaphylatoxins

C3b

opsonization and phagocytosis

C5b-9:

MAC complex

What recognizes microbes and dead tissues?

TLR
NFM receptors
Receptors for opsins
Cytokine receptors

Phagocytosis steps

Recognition
Engulfment
Killing

Opsonization

recognition

• opsonins attach to microbes which help wbcs better recognize microbes to destroy them
• major: C3b, IgG, Mannose binding lectin

Ingestion

• ingestion: phagosome + lysosome = phagolysosome
• dependent on polymerization of actin

Killing

• ROS
• NADPH oxidase oxidize NADPH and reduce oxygen to anion

Superoxide dismutase:

• reduces H202
  Myeloperoxidase:
• in neutrophils combines with Cl- and converts H202 to bleach which kills

Types of acute inflammation

Serous: fluid buildup (blister)

Fibrinous: increased permeability - exudate type - increased fibrin deposition (fibrinous peritonitis)

Suppurative (purulent)

• pus
• pyogenic bacteria (staph), abscesses

Ulcer

• excavation of surface of tissue because of shedding of inflamed necrotic tissue

Outcomes of termination of acute inflammation

• complete resolution: minor injury, stable cells

• tissue destruction and extensive injury: healing by scar

• progression to chronic inflammation

Chronic inflammation cases

Persistent infections; response of prolonged duration
(weeks/months)
• Tissue destruction with attempts at healing
• Infiltration by mononuclear cells
• Immune-mediated inflammatory diseases
• Prolonged exposure to toxins

Monocytes and macrophages

becomes dominant cell by 48 hours

• after neutrophils
• tissue macrophages can live months or years

Acute and chronic inflammation cells dominate?

Lymphocytes: predominate in viral infections

ACUTE: neutrophils predominate *bacterial

• respond quicker, more firm adhesion
• short lived

Cells appearance in inflammation

Neutrophils (most predominant around 24 hours) , macrophages (most predominant around 48 - 72 hours)

T vs B lymphocytes

T lymphocytes:

• progenitor in bone marrow, mature in thymus
• rearragnement to become CD4 and CD8

B lymphocytes:

• Immature B cells produced in bone marrow
• express IgM and IgD

Activated macrophages in chronic inflammation pathways

Classically activated

• interferon gamma
• kills in acute ROS
• chronic: secretes cytokines

Alternatively activated:
promotes growth factors

• TGF beta
• IL10

Cytokines released by T lymphocytes

TH1 produce IFN gamma activate macrophages
TH2 produce IL4, 5, 13 activate eosinophils
TH17 produce IL17 activate neutrophils

lymphocytes + macrophages = bidirectional

Granulomatous inflammation

• chronic: attempt to contain offending agent difficult to eradicate
• MTB
  necrotizing vs non-necrotizing
• secrete IL2 which perpetuate response by increase secretion of IFN gamma

Granuloma

aggregate of macrophages

• surrounded by rim of lymphocytes
• giant cells

common in TB and fungi

isolates foreign substances unable to eliminate

Eosinophils

allergies, asthma, parasites

• mediated by IgE
• MBP: toxic to parasites
• lysis

Cells involved in chronic inflammation

macrophages and lymphocytes

Cardinal Signs of Inflammation (Mnemonic): "PRISH"

• Pain – Prostaglandins, Bradykinin

• Redness (Rubor) – Vasodilation (Histamine, NO)

• Immobility (Functio Laesa) – Loss of function due to swelling and pain

• Swelling (Tumor) – Vascular leakage

• Heat (Calor) – Increased blood flow

Granulomatous inflammation types

- Caseating: Central necrosis (e.g., TB)

- Non-caseating: No necrosis (e.g., Sarcoidosis)

Margination

Neutrophils move to vessel periphery due to stasis

Rolling

Neutrophils slow down via selectin-mediated interactions (low affinity binding)

Adhesion

Integrins on neutrophils switch to high-affinity binding and adhere firmly to ICAM-1 on endothelial cells

Transmigration (Diapedesis)

Neutrophils pass between endothelial cells via PECAM-1 (CD31)

Chemotaxis

Directed migration towards chemical attractants

Recognition CC

Defective opsonization: Bruton's Agammaglobulinemia

Engulfment CC

Defect: Chediak-Higashi Syndrome (microtubule dysfunction)

Killing CC

Chronic Granulomatous Disease (NADPH oxidase deficiency)