Acute Inflammation Flashcards
What is inflammation?
A well ordered vascular and cellular response of tissues to aggression.
• It is a defense mechanism to eliminate initial cause of injury and the consequences of that injury (i.e necrotic cells) and initiate repair
What are the two components of acute inflammation?
Vascular: Vascular component characterized by hyperemia, vasodilation and vascular leakage. This is to “dilute” the cause of injury.
Cellular: Cellular component is to heal/ repair the injury
What is a consequence of inflammation?
• Potential for substantial tissue damage. Sometimes the inflammation will cause a worse injury.
What is the purpose of inflammation?
- contain injury
- destroy/ dilute or wall off offending agents
- remove damaged or necrotic tissue (macrophages)
- prepare tissue for repair / healing
What are the beneficial aspects of inflammation? The harmful aspects of inflammation?
- Good: Diluting and/or inactivating biological
and chemical toxins. Killing or sequestering microbes,
foreign material, necrotic tissue, and neoplastic cells. Providing wound healing factors. Restricting movement for healing and repair
• Bad: Prolonged release of inflammatory mediators, excessive fibrosis, hypersensitivity and autoimmunity, chronic inflammation can lead to neoplastic transformation,
What are the 5 cardinal signs of inflammation?
◦ Heat and redness (Hyperemia and vasodilation)
◦ Swelling ( edema and emigration of leukocytes)
◦ Pain (chemical mediators)
◦ Loss of function ( can preserve tissue and allow for healing)
What are the vascular changes associated with acute inflammation?
- Vascular: Hyperemia, Vasodilation, Increased vascular permeability (edema)
- Cellular: - Emigration of leukocytes (predominantly neutrophils) and delivery at the site of injury, to kill and/or neutralize the inciting stimulus
What orchestrates cellular and vascular changes of acute inflammation?
• Cellular and vascular changes are orchestrated by chemical mediators (many of them)
What is the clinical definitions of inflammation? Pathologic definitions? What is seen in subacute inflammation?
Clinical definition
• Acute: Hours to days
• Chronic: weeks to months to years
Pathologic definition
• Acute: edema, fibrin, neutrophils
• Chronic: macrophages, lymphocytes, plasma
cells, few neutrophils, fibrosis
Subacute: Lymphocytes and Plasma cells.
What is the general process of acute inflammation?
- Bacteria and other pathogens enter wound
- Macrophages “senses” bacteria through their receptors and phagocytize
- Chemical mediators secretion by activated
macrophages and mast cells 4. Hyperemia, vasodilation and increase vascular permeability - Leakage of fluid (edema) and neutrophils
- Neutrophils phagocyte and/or secrete
granules that kill and degrade pathogens - Macrophages secrete cytokines that attract leukocytes to the site and activate cells involved in tissue repair
- Inflammatory response continues until the foreign material is eliminated and the
wound is repaired
What are the causes of acute inflammation?
• Infections (bacteria, viruses, parasites)
• Trauma
• Physical agents (heat, cold)
• Toxins
• Tissue necrosis (of any origin; products of degenerate or
neoplastic processes)
• Foreign bodies (grass awn, sutures)
• Immunological reactions
What are the primary vascular and cellular responses during acute inflammation?
- Mast cell will sense injury and will secrete cytokines that will increase vascular permeability, endothelial cell contraction, chemotaxis of neutrophils.
- Diapedesis of erythrocytes can also occur - mild hemorrhage.
What occurs during the fluidic phase of acute inflammation? What is the purpose?
1) Increase blood flow (hyperemia) and vasodilation (mediated by Histamine, NO, PGD2, Bradykinin, LTB4) 2)↑Vascular permeability (mediated by Histamine, Bradykinin, C5a, C3a, PGE2, Leukotrienes, PAF, IL-1, TNF)
- Leads to leakage of fluid, plasma proteins and leukocytes (neutrophils) to the tissue
- Exudate
- Purpose: Dilute, isolate (surround), and trap (contain) the injurious agent and damag
What is transudate? What is exudate?
• Transudate - accumulation of fluid- clear, watery, translucent, low protein/ plasma cells.
◦ Think of mechanism of edema, increased hydrostatic (CHF), decreased osmotic (parasitism, PLN, PLE, Liver failure), lymphatic obstruction (tumors)
• Exudate: inflammation, accumulation of opaque, thick fluid. A lot of plasma proteins, neutrophils, macrophages, inflammatory cells, ect. Mechanism is increased vascular permeability.
◦ Fibrin also present due to decreased vascular permeability
What mediates increased vascular permeability?
• Mediated by vasoactive amines (histamine, bradykinin), C5a and C3a, prostaglandins, leukotrienes, PAF, IL-1 and TNF
What are the mechanisms of increased vascular permeability?
1) Retraction of endothelial cells
2) Direct endothelial cell injury 3) Leukocyte-mediated vascular injury
4) Increased transcytosis
What occurs during retraction of endothelial cells?
• Mediated by vasoactive amines
• most common
• Gap formed between endothelial cells to allow fluid and plasma cells to leak out.
- Mediated by vasoactive amines
(histamine, bradykinin, serotonin), NO,
IL-1 and TNF
What occurs during direct endothelial cell injury?
• can cause necrosis, and detachment of cell from underlying basement membrane
• activation of platelets, clotting and complement cascades
• Thermal injury, chemotherapeutic drugs, radiation, bacterial cytotoxins, viral and protozoal infections
◦ Protozoa can cause vasculitis, ect
What occurs during leukocyte mediated vascular injury?
- can cause necrosis, and detachment of cell from underlying basement membrane
- Neutrophils/ other leukocytes attach to endothelial cells and release ROS and proteolytic enzymes ( from lysosomes)
• usually associated with bacteria, or viruses that affect neutrophils.
- Ricckketsia is one example. RMSF
What is the end result of increased vascular permeability? What is fibrin?
- end results are fibrin, strands of fibrin.
- Fibrinous pleuritis.
- Fibrin is chemoattractant to neutrophils
- If inflammation does not resolve or if it is exacerbated by chemical mediators (pro- inflammatory cytokines), there will be accumulation of neutrophils
What is seen in this image?
Fibrin : Fibrinous pleuritis
What is seen in this image?
Fibrinosuppurative pleuritis
**Fluidic and cellular phase occur together
What is the purpose of cellular phase of acute inflammation? What is the result?
• Purpose of cellular phase: Deliver leukocytes into the exudate so they can kill and/or inactivate the stimulus
Results in:
- Exudation
- Cellular activation
• Microbial killing ( by phagocytosis, or release of proteolytic degradative enzymes)
• Extent/ intensity of this process causes varying degrees of injury to adjoining normal tissue.
- Clear necrotic cells and debris
What are the steps of the leukocyte adhesion cascade? What is it mediated by?
1) Margination
2) Rolling
3) Activation and Stable Adhesion
4) Transendothelial cell migration
Mediated by adhesion molecules and cytokines/chemokines (histamine, TNF, IL-1):
- Selectins (Rolling)
- Integrins + VCAM and ICAM (Activation and Stable Adhesion)
- PECAM and JAM (Transendothelial cell migration)
What drive migration of leukocytes to the site of inflammation?
- migration driven by chemokines
- chemokines: bacterial products, IL-8, complement components (C5a and C3a) and arachadonic acid metabolites ( LTR4) (act as GPS for neutrophils)
- Produced at sites of inflammation and diffuse out into surrounding tissues.
- Activates leukocytes.
What occurs once neutrophils enter the site of inflammation?
Kill pathogens and degrade foreign material by two mechanisms:
– Phagocytosis (ROS)
– Secretion of granule contents into the exudate (can contribute to tissue injury)
- Enzymes (proteases) - Myeloperoxidases (MPO) - Matrix metalloproteinases - Lactoferrin lysozyme
What are the effector cells of acute inflammation?
- Endothelial cells
- Mast cells and basophils
- Neutrophils
- Eosinophils
- NK cells Macrophage
- Monocytes and Macrophages
What are the cell derived mediators of inflammation? Plasma protein derived mediators?
– Preformed (in granules)
• Histamine
– Synthesized
- Prostaglandins
- Leukotrienes
- Cytokines and Chemokines
- Platelet-activating factor (PAF)
- Reactive oxygen species
- Nitric oxide
What are archidonic acid metabolites (lipid mediators)? What are the sources? What pathwayas are they formed in?
Arachidonic Acid Metabolites (Lipid Mediators): Prostaglandins, Thromboxanes, Leukotrienes and Lipoxins
Sources: Resident cells, leukocytes, mast cells, eosinophils
Cell injury → Increase intracytoplasmic Ca++ concentration → activation of phospholipase A2
• Cyclooxygenase pathway → Prostaglandins and Thromboxanes
- 3 COX isoenzymes (COX1= constitutively expressed; COX2= induced by inflammatory stimuli; COX3= splice variant of COX1, can cross BBB)
- Lipoxygenase pathway → Leukotrienes and lipoxins
What will inhibit phospholipase? What are Cox-1 and Cox 2 inhibitors? what does PGI2, TXA2, PGD2, PGE2, 5-lipoxygenase, and lipoxin A4 and B4 do?
Steroids will inhibit phospholipase
COX -1 and COX 2 inhibitors: aspirin, indomethacin, inhibit)
Immunosuppressive and anti inflammatory drugs will inhibit.
COX-2 to prostaglandins.
PGI2 -> Causes vasodilation, inhibits platelet aggregation.
TXA2 -> causes vasoconstriction, promotes platelet aggregation.
PGD2, PGE2 -> causes vasodilation, increased vascular permeability.
5-Lipoxygenase -> leukotrienes ( C4, D4, E4 - in cases of asthma (bronchospasm , increased vascular permeability.
lipoxin A4, and B4 ( inhibition inflammation , during healing)
What is the roles of cytokines TNF, IL-1, IL-6?
• Sources: Resident cells, leukocytes, mast cells, eosinophils
• Most important roles:
– Endothelial activation: Both cause increased expression of endothelial adhesion molecules (selectins and ligands for WBC integrins)
– Activation of WBCs and other cells:
• TNF augments response of neutrophils and stimulates microbicidal activity of
macrophages
– Systemic acute-phase response: TNF & IL-1 (along with IL-6) induce systemic acute- phase response associated with infection or injury
- Increased production: C-reactive protein, Fibrinogen, Hepcidin, others - Stimulate innate immune system against infection
Decreased abumin production
What can TNF, IL-1 cause?
Insulin resistance
What is the most important part of the reparative phase? What categories of tissue repair are possible?
• Macrophage movement into areas of entrapped
stimulus/inciting agent to further process and remove cellular debris
• Macrophage release molecules initiating tissue repair
Macrophages most important
- Tissue repair may be (1) regenerative or by (2) scarring (fibrosis)
1 - Mild tissue injury with preservation of supporting stroma
and basement membrane: Regeneration
2 - Tissue injury with destruction of supporting stroma and
basement membrane: Scarring (fibrosis)
What cells are considered labile? Stable? Permenant?
• Labile: Bone marrow stem cells, GI epithelium, keratinocytes
- Always Regenerating
• Stable: Hepatocytes, renal tubular epithelium - Sometimes regenerating
• Permanent: Neurons, skeletal and cardiac muscle
- Never regenerating
What are the potential outcomes of acute inflammation?
- outcome depends on damage severity and location
- mild -> Resolution
- moderate: Healing by repair
- Severe : Chronic inflammation
What occurs in resolution? What are characteristics of resolution?
• Short-term damage
• Little tissue destruction with regeneration
- Tissue stroma and basement membrane are intact
• Removal of cellular debris by macrophages
What causes healing by fibrosis?
• Substantial tissue destruction, without regeneration capacity, or abundant exudation of fibrin.
What is occuring in this image?
Fibrosis
What is occuring in this image?
Healing by fibrosis
What is occuring in this image?
Abcess formation
What is the type of lesions in this image?
Offending agents have not been removed ( tuberculosis) so their ar multiple granulomas seen in this section of tissue.
What kind of exudate is seen in this image?
Serous
What is seen in these images?
Mucoid or Catarrhal exudate
What is seen in this image?
Fibrinous exudate
What is suppurative exudate?
Exudate with a large number of neutrophils
What kind of exudate is seen in this image?
Suppurative (purulent discharge) Abcess
What is occuring in this image?
Mucupurulent exudate
What is occuring in this image of tissue?
Hemorrhagic exudate
What is necrotizing exudate?
- An acute inflammatory reaction in which the predominant change is necrosis
- tissue response of necrosis -> this picture is herpes virus
- All white dots are areas of necrosis with areas of inflammatory cells.
What is occuring in this image?
Fibrinonecrotic (pseudomembranous)
How would you categorize the tissue in this image?
Necrohemorrhagi
What can you see in necrosis of muscle fibers?
Necrosis of muscle fibers + emphysema
What is occuring in this histology section of tissues?
Hemorrhage
What is occuring in this image? What step is it in the leukocyte adhesion cascade?
Margination
• With vasodilation and reduced blood flow, leukocytes exit the central region of the vascular lumen and
move to the periphery near the endothelial cell surface
What occurs during the rolling stage of leukocyte adhesion?
• Initial contact between leukocytes and endothelial cells
• Transient, weak binding interactions between Selectins (adhesion molecules) and their
receptors
• Under the influence of cytokines (histamine, TNF, IL-1), endothelium express P-selectin and E-
selectin
• Reduces the velocity of the travelling leukocyte, creating the microenvironment for activation
and “stable adhesion” (the next step)
What occurs during the activation and stable adhesison step of leukocyte adhesion? What needs to be activated for it to occur?
- For stable adhesion to occur, neutrophils and endothelial cells need to become activated
- Activation is mediated by cytokines (IL-1, TNF) and chemokines (IL-8)
• Activation is characterized by expression of INTEGRINS on leukocytes and vascular cell adhesion
molecule (VCAM) and intercellular adhesion molecule (ICAM) on endothelial cells.
• Stable adhesion: Binding of INTEGRINS on leukocytes to VCAM and ICAM on endothelial cells
What occurs during the transendothelial cell migration (emigration) step of the leukocyte adhesion cascade?
• Firmly adhered leukocytes emigrate across the endothelial layer by passing between endothelial cells
• Mediated by expression and binding of Platelet endothelial cell adhesion molecule 1 (PECAM-1) and
junctional adhesion molecules (JAM) on both leukocytes and endothelial cells
What is leukocyte adhesion deficiency? What animals can it be seen in? What are the clinical signs?
• Holstein Cattle, dogs (Irish setters), and human
beings with LAD lack functional expression of
the β2 integrins
• High numbers of neutrophils, exceeding 125,000/μL
in the blood
• Oral ulcers, gingivitis, tooth loss, enteric ulcers,
cutaneous ulcers, abscesses that lack pus formation,
and pneumonia
Where do leukocytes migrate too during inflammation? What are the main chemoattractants?
- Migration to extracellular matrix ( to site of inflammation)
- Migration via chemoattractant substances (chemotaxis)
• Main chemoattractant substances: bacterial products, chemokines (IL-8), complement components
(C5a), arachadonic acid metabolites (LTB4)
- They are produced at sites of inflammation and diffuse out into the surrounding tissues
- Also activate leukocytes and get them ready for battle
What are the 3 steps of phagocytosis?
• 1. Recognition and attachment - Facilitated by opsonins (C3b and IgG)
• 2. Engulfment - Form a phagosome and fuse with lysosome = phagolysosome
• 3. Killing/degradation
- Lysosomal enzymes (acid hydrolases, proteases)
- Oxidative (Respiratory) burst: formation of ROS
- Formation of NO
- Release of granule contents: myeloperoxidase (absent in avian and reptiles), elastase, collagenase, lysozyme, defensins, etc…)
- Releasing of these granules into the extracellular space leads to tissue damage
What is the role of mast cells and basophils in acute inflammation?
• Located around small blood and lymphatic vessels of skin and mucous membranes
• Both MCs and basophils play a role in IgE-mediated hypersensitivity reactions
•Degranulation → Mucus secretion, bronchoconstriction, vasodilation, fluid accumulation in airways
•Granules → Preformed/Synthesized Mediators: Histamine, Chymase and Tryptase (degradation of ECM),
cytokines, growth factors, PAF, LTC4, PGD2…
What is the role of neutrophils in acute inflammation?
• First leukocytes to enter the exudate:
– Kill microbes (bacteria, fungi, protozoa, viruses)
– Kill tumor cells
– Eliminate foreign materials • Kill pathogens and degrade foreign material by two mechanisms:
–Phagocytosis → fusion with lysosome
– Secretion of granule contents into exudate (can contribute to tissue injury) • Activated leukocytes (including neutrophils) also produce cytokines
What is the roll of eosinophils in acute inflammation? What are the chemoattractants for eosinophils ?
• Recruited in response to allergic or parasitic disease; often come in transition from acute→chronic
inflammation
– Worms, wheezes & weird diseases
• When activated, eosinophils can also elaborate:
– CKs, Chemokines, proteases, oxidative radicals • Eosinophil chemoattractants (released from epithelial cells, eosinophils, mast cells, and helminths):
– Histamine – C5a – Eotaxin – Cytokines (IL-4, Il-5, IL-13)
What is the role of natural killer cells?
• NK cells: Lysis/apoptosis of tumor & virus infected cells without previous
encounter by releasing perforin & granzymes
• MHC class I (ubiquitous expression by normal cells) is inhibitory - prevents
NK cells from killing host cells
– If MHC I is downregulated by pathogen → NK can kill the cell – Virus-infected and neoplastic cells often downregulate MHC1→ susceptible to NK mediated lysis
• All other nucleated cells express MHC I and are protected
What is the role of monocytes/ macrophages in acute inflammation? What are the 2 types of tissue macrophages? What is its role in inate and adaptive immunity?
• During AI, monocytes express receptors for chemical mediators → migration, chemotaxis, etc→ once in
lesion, receptors bound by inflammatory mediators → mature into macrophages
• Tissue macrophages (2 types):
– Reside within specific organs/tissues
• Histiocytes, alveolar macrophages, Kupffer cells, osteoclasts, microglial cells
– Derived from monocytes
- Inflammation: Monocyte receptors bound by CKs, antigens, etc→ maturation to macrophages
- Part of innate immunity: Phagocytosis, release CKs
- Adaptive immunity: APC, T-lymphocyte regulation
What are the 3 pathways of complement activation? What activates them?
• Classic pathway
- Activated by antibody complexes: IgG or IgM bound to Ag
• Lectin pathway
- Plasma mannose-binding lectin bind to carbohydrates on microbes
• Alternative pathway
- Activated by products from microbes (LPS, endotoxin, fungal cell wall polysaccharides), venom
