Inflammation Flashcards
What is inflammation?
Blood components (inflammatory cells, plasma proteins and fluid) exiting the vessel into the interstitial space
What is the purpose of inflammation?
Remove/eliminate cause of infection (pathogen) or clean up necrotic tissue
What are the two major patterns of inflammation?
-Acute (immediate with limited specificity)
-Chronic
List the 4 causes of inflammation
- Infections: (bacterial, viral, fungal, parasitic) and microbial toxins cause distinct patterns of inflammation
- Tissue necrosis: causes inflammation regardless of cause
- Foreign bodies: exogenous (dirt from trauma and bugs it carries) and endogenous (urate crystals-gout, cholesterol crystals-athersclerosis)
- Immune reactions (hypersensitivity): autoimmune diseases (against self) and environmental substances (allergies or microbes)
Cells have receptors to sense microbes and “smell” dead cells and their products. List these receptors.
-Toll-Like Receptors (TLR)
-Inflammasome
-Complement-plasma proteins that recognize and destroy blood-borne microbes
Where can you find Toll-Like Receptors (TLRs)?
Present on cell membrane of the innate immune system (ex: macrophages and dendritic cells) and on endosomes
How are TLRs activated?
By pathogen-associated molecular patterns (PAMPS) that are commonly shared by microbes
-CD14 (a TLR) on macrophages recognize lipopolysaccharide (a PAMP) on the outer membrane of gram-negative bacteria
TLR activation results in upregulation of ________, a nuclear transcription factor that activates immune response genes leading to production of _______
NF-KB; multiple immune mediators
TLRs are also present on cells of adaptive immunity and hence, play an important role in mediating _________
chronic inflammation
What is inflammasome and what is its function?
-Multiprotein cytoplasmic complex
-Senses dead cell products (uric acid, ATP from damaged mitochondria, etc.) and induces activation of IL-1 –> leukocyte recruitment
List the two types of mediators in regards to acute inflammation
Cell-derived
-arachidonic acid (AA) metabolites
-mast cell products
-cytokines
Plasma-protein derived
-complement
-hageman factor- kinin system activation
What is the function of and what is the source of this mediator?
Histamine
Source: mast cells, basophils, platelets
Fxn: Vasodilation, increased vascular permeability, endothelial activation
What is the function of and what is the source of this mediator?
Prostaglandins
Source: AA
Fxn: cardinal signs of acute inflammation
What is the function of and what is the source of this mediator?
PGI2 (prostacyclin), PGE1, PGE2, PGD2
Source: Mast cells, leukocytes
Fxn: Vasodilation, pain, fever
What is the function of and what is the source of this mediator?
Thromboxane A2 (TXA2)
Source: Platelets
Fxn: Vasoconstriction, platelet aggregation
What is the function of and what is the source of this mediator?
Leukotrienes
Source: Mast cells, leukocytes
Fxn: Increased vascular permeability, chemotaxis, leukocyte adhesion, and activation
What is the function of and what is the source of this mediator?
TNF
Source: Macrophages and dendritic cells, mast cells, T lymphocytes
Fxn: Activates endothelium (increase adhesion molecules) and secretion of other cytokines and chemokines; systemic effects*. Mediates cachexia
What is the function of and what is the source of this mediator?
IL-1
Source: Macrophages and dendritic cells, endothelial cells, some epithelial cells
Fxn: Similar to TNF, also stimulates formation of Th17 (makes IL-17)
What is the function of and what is the source of this mediator?
IL-6
Source: Macrophages, other cells
Fxn: Systemic effects (acute phase response)
What is the function of and what is the source of this mediator?
Chemokines
Source: Macrophages, endothelial cells, T lymphocytes, mast cells, other cell types
Fxn: Recruitment of leukocytes to sites of inflammation; migration of cells in normal tissues
What is the function of and what is the source of this mediator?
IL-17
Source: T lymphocytes
Fxn: Recruitment of neutrophils and monocytes
What is the function of and what is the source of this mediator?
IL-12
Source: Dendritic cells, macrophages
Fxn: Increased production of IFN-gamma
What is the function of and what is the source of this mediator?
IFN-gamma
Source: T lymphocytes, NK cells
Fxn: Activation of macrophages (increased ability to kill microbes and tumor cells)
What is the function of and what is the source of this mediator?
IL-17
Source: T lymphocytes
Fxn: Recruitment of neutrophils and monocytes
What is the function of and what is the source of this mediator?
IL-4
Source: T lymphocytes
Fxn: Activates macrophages (alternative pathway to promote repair) and eosinophils
What is the function of and what is the source of this mediator?
IL-13
Source: T lymphocytes
Fxn: Activates macrophages (alternative pathway to promote repair) and eosinophils
What is the function of and what is the source of this mediator?
IL-10
Source: macrophages
Fxn: Downregulate inflammation (negative feedback)
What is the function of and what is the source of this mediator?
TGF-beta
Source: macrophages
Fxn: downregulate inflammation (negative feedback)
What is the function of and what is the source of this mediator?
Platelet-activating factor
Source: Platelets, PMNs, macrophages mast cells, endothelial cells
Fxn: Platelet aggregation, vasoconstriction, bronchoconstriction. At low levels causes vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
What is the function of and what is the source of this mediator?
Complement
Source: Produced in liver
Fxn:
-C5a: leukocyte chemotaxis
-C3a, C5 anaphylatoxins: mast cell degranulation
-C3b: opsonin for phagocytosis
-C5b, C6-C9: direct cell lysis through membrane attack complex
What is the function of and what is the source of this mediator?
Kinins
Source: Produced in liver, activated by Hageman Factor (Factor XII) leads to production of bradykinin
Fxn: Increase vascular permeability, smooth muscle contraction, vasodilation, pain
What is the function of and what is the source of this mediator?
Nitric Oxide
Source: Multiple cells
Fxn: Vasodilation of vascular smooth muscle
Arachidonic aid (AA) metabolites is released from the phospholipid cell membrane by ____________ and then acted upon by __________ or _________
phospholipase A2; cyclooxygenase or 5-lipoxygenase
Cyclooxygenase produces ________ and ________
Prostaglandins (PG) and Thromboxane A2 (TXA2)
PGI2, PGD2, and PGE2 mediate…..
vasodilation (at the arteriole) and increased vascular permeability (at the post-capillary venule)
PGE2 also mediates….
pain and fever
PGI2 inhibits ________ while TXA2 causes ________
platelet aggregation; vasoconstriction platelet aggregation
5-lipoxygenase produces ________
leukotrienes (LT)
LTB4 attracts (chemotaxis) and activates _______
neutrophils
LTC4, LTD4, and LTE3 (slow reacting substances of anaphylaxis) mediate……
vasoconstriction, bronchospasm, and increased vascular permeability
What is the function of Lipoxins?
Inhibit neutrophil chemotaxis and adhesion (counteracts LTB4)
What do Corticosteroids inhibit?
Phospholipase
What do NSAIDS inhibit?
cyclooxygenase (COX)
-COX-1 is expressed in most tissues and increased during inflammation
-COX-2 is absent from most normal tissues and is induced during inflammation
What are the COX-1 inhibitors?
Aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve)
What are the COX-2 inhibitors?
Celebrex
What is used to treat asthma?
Lipoxygenase inhibitors, and leukotriene receptor antagonists
Where are mast cell products widely distributed?
Throughout connective tissue
List the 3 things mast cell products are activated by
1) Tissue trauma
2) Complement proteins C3a and C5a
3) cross-linking of cell surface IgE by antigen
Immediate response involves release of preformed histamine granules, which mediate….
vasodilation of arterioles and increased vascular permeability
Delayed response involves production of arachidonic acid metabolites, particularly leukotrienes. What does this prolong?
The inflammatory response over hours
What are cytokines?
Proteins secreted mainly by activated lymphocytes, macrophages, and dendritic cells but also endothelial, epithelial and CT cells
What are the major players in acute inflammation?
TNF, IL-1, IL-6
What is the function of TNF and IL-1
Activate endothelium, induce secretion of other cytokines and chemokines and together with IL-6 promote systemic inflammatory state: fever, lethargy, and stimulate the liver to make acute phase proteins
*TNF also causes metabolic wasting
What is the function of chemokines?
Cytokines that act as chemotactic agents for various inflammatory cells
What are the major players in chronic inflammation?
IFN-gamma, IL-12, IL-17
(but mediators of acute inflammation also influence)
What cytokines are involved in negative feedback to downregulate inflammation
IL-10, TGF-beta
Describe Nitric Oxide (NO)
short lived, free radical made by multiple cells
When made by endothelium: relaxes vascular smooth muscle causing vasodilation
Describe the complement pathway
Proinflammatory serum proteins that “complement” inflammation. Circulate as inactive precrusors
List the 3 ways activation of the complement pathway occurs
-Classical pathway
-Alternative pathway
-Mannose-binding lecting (MBL)/ pathway
What is the classical pathway?
C1 binds IgG or IgM that is bound to antigen
What is the alternative pathway?
Microbial products directly activate complement without Antigen/Ab complexes
What is Mannose-binding lectin (MBL) pathway?
MBL binds to mannose on microorganisms and activates complements
All pathways in the complement pathway result in production of….
C3 convertase (mediates C3 –> C3a and C3b), which, in turn, produces C5 convertase (mediates C5 –> C5a and C5b). C5b complexes with C6-C9 to form the membrane attack complex (MAC)
What is the function of C3a and C5a (anaphylatoxins)
Trigger mast cell degranulation (histamine release –> vasodilation, increased vascular permeability), activate leukocytes
What is the function of C5a?
chemotactic for neutrophils (more potent than C3a)
What is the function of C3b
Opsonin for phagocytosis
What is the function of the MAC?
Lyses microbes by creating a hole in the cell membrane
What is Hageman Factor (Factor XII)?
-Inactive proinflammatory protein produced in liver
What is Hageman factor activate by? What does it activate?
Activated upon exposure to subendothelial or tissue collagen; in turn, activates:
-Coagulation and fibrinolytic systems
-Complement
-Kinin system
What is the Kinin system?
Kinin cleaves high-molecular weight kininogen to bradykinin, which mediates vasodilation and increased vascular permeability (similar to histamine) as well as pain
What are the principal mediators of vasodilation?
Histamine
Prostaglndins
What are the principle mediators for increased vascular permeability?
Histamine
C3a and C5a
Leukotrienes C4, D4, E4
What are the principal mediators for chemotaxis, leukocyte recruitment and activation?
TNF, IL-1
Chemokines
C3a, C5a
Leukotriene B4
What are the principal mediators for a fever
IL-1, TNF
Prostaglandins
What are the principal mediators for pain
Prostaglandins
Bradykinin
What are the principal mediators for tissue damage
Lysosomal enzymes of leukocytes
Reactive oxygen species
What are TNF-alpha inhibitors used for?
To treat psoriasis and other skin conditions, rheumatoid arthritis, inflammatory bowel disease (i.e. Crohn disease)
What are IL-17 inhibitors used for?
Psoriasis
Define chronic inflammation
Long-term (weeks-months-years) inflammation that can, but doesn’t always, progress from
acute inflammation
(T/F) in chronic inflammation, Inflammation, tissue injury, and repair all occur simultaneously
True
What are the three major characteristics of chronic inflammation?
- Infiltration of tissue with mononuclear
“chronic inflammatory” cells (macrophages,
lymphocytes, plasma cells) - Tissue destruction caused by the products
of chronic inflammatory cells - Repair involves new vessel formation
(angiogenesis) and fibrosis
When does chronic inflammation occur?
- Persistent infections
- Prolonged exposure to potentially toxic
agents - Autoimmune diseases
What are the four chronic inflammatory cells?
macrophages, lymphocytes, plasma cells and eosinophils
How do macrophages (MACs) form?
- Monocytes in blood arise as precursors in bone marrow
- Circulate in blood for about 1 day; migrate to site of acute inflammation within 24-48 hrs, peaking at 2-3 days of onset → When leave the bloodstream, called macrophages.
How do macrophages arrive at site of inflammation?
Arrive in tissue like PMNs via the margination, rolling, adhesion, and transmigration sequence
How do macrophages rid the body from the foreign entities?
Ingest organisms via phagocytosis (augmented by opsonins) and destroy phagocytosed material using similar mechanisms as PMNs
What is the fate of macrophages?
- Eventually die or are resorbed in lymphatics
- In chronic inflammation, can fuse into multinucleated giant cells
What are tissue macrophages (MACs)?
Tissue macrophages (not derived from
circulating monocytes) are part of the
mononuclear phagocyte or reticuloendothelial
system in most CT and organs
What is a tissue macrophage referred to in the:
Liver
Spleen/LN
CNS
Lung
Liver: Kuppfer cells
Spleen/LN: Sinus histiocytes
CNS: Microglial cells
Lung: Alveolar macrophages
Macrophages help regulate the three potential outcomes of the inflammatory process. These are:
- Continue the acute response
- Resolution and healing
- Induce chronic inflammation
Macrophages continue the acute response through release of mediators (_____,_____) to recruits additional PMNs, macrophages.
TNF, IL-1
Macrophages help in the resolution and healing of inflammation through release of ____________ (e.g., ______ and ______)
anti-inflammatory cytokines, (IL-10, TGF-β)
Macrophages help Induce chronic inflammation through _____________ and activation of ___________, which secrete ________ that promote chronic inflammation.
antigen presentation, CD4+ helper T cells, cytokines
MAC activation can happen through one of two ways, _____________ pathway or _____________ pathway
classical, alternative
The classical pathway is induced by ________, ________, and ________
microbial products (LPS), T cell signals (e.g. IFN-γ), and foreign substances
MACs in the classical pathway produce __________, _____ and ______ which help
kill microbes and stimulate inflammation
lysosomal enzymes, NO, ROS
The alternative pathway is Induced by ____ and ____ from T cells and other cells
IL-4, IL-13
(T/F) Macrophages in the alternative pathway directly attack microbes
False. They help in repair by secreting growth
factors (TGF-β)
TGF-β promote __________, _____________, and ________________
angiogenesis, fibroblast activation, collagen synthesis
Lymphocytes respond to specific stimuli (i.e._______) as well as ____________ or __________
infections, ischemic necrosis, trauma
_________ are the major driver of autoimmune or chronic inflammatory diseases
Lymphocytes
_________ may develop into plasma cells (make
antibody)
B cells
__________, upon activation, make cytokines
CD4+ T cells
CD4+ T cells make ____, ____, or ____
TH1 cells, TH2 cells, TH17 cells
TH1 cells produce _____ which stimulate the _____ pathway for MACs
IFN-γ, classical
TH2 cells secrete _____ and _____ which activate ________ and stimulate the ________ pathway for
MACs
IL-4, IL-13, eosinophils, alternative
(Important in allergic inflammation and in defense against parasites)
TH17 cells secrete ____ which recruits _____
and _________
IL-17, PMNs, monocytes
What are the cardinal signs of acute inflammation?
-Redness (rubor)
-Warmth (calor)
-Swelling (tumor)
-Pain (dolor)
-Fever
What causes redness (rubor) and warmth (calor)?
-Due to vasodilation, which results in increased blood flow
-Occurs via relaxation of arteriolar smooth muscle; key mediators are histamine, prostaglandins, and bradykinin
What causes swelling (tumor)?
Due to increase vascular permeability causing leakage of fluid from postcapillary venules into the interstitial space
What causes pain (dolor)?
Bradykinin and PGE2 sensitize sensory nerve endings
What causes fever?
-Pyrogens cause macrophages to release IL-1 and TNF, which increase COX activity in perivascular cells of the hypothalamus
-This leads to increased PGE2 which raises temperature set point
Describe the features of acute inflammation
-Immediate and early response to injury
-Short-term (minutes to hours)
-Tissue infiltration by neutrophils (this is the hallmark cell of acute inflammation!)
List the correct steps of vascular changes (of acute inflammation??)
- Brief vasoconstriction
- Vasodilation
- Increased permeability
- Exudate leaving the circulation
- Increase in blood viscosity
- Decrease in blood flow through the microcirculation
List the steps of cellular events (PMNs)
- Margination
- Rolling
- Adhesion
- Transmigration and chemotaxis
- Phagocytosis
- Destruction of phagocytosed material
- Resolution
Describe Step 1: Margination
-Vasodilation of arterioles slows blood flow
-Cells marginate from center of flow to the periphery
Describe Step 2: Rolling - loose attachment
-Selectin “speed bumps” are upregulated on endothelial cells (P-selectin release from Weibel-Palade bodies is mediated by histamine and E-selectin is induced by TNF and IL-1)
-Selectins bind Sialyl-Lewis X on leukocytes
-Interaction results in rolling of leukocytes along vessel wall
Describe Step 3: Adhesion
-Cellular adhesion molecules (ICAM and VCAM) are upregulated on endothelium by TNF and IL-1
-Integrins becomes high affinity and are upregulated on leukocytes by C5a and LTB4
-Interaction between CAMs and integrins results in firm adhesion of leukocytes to the vessel wall
-Leukocyte adhesion deficiency: often a defect in integrins (clinically increased circulating neutrophils and recurrent bacterial infections that lack pus formation)
Describe step 4: transmigration and chemotaxis
-Leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants (chemotaxis)
-Neutrophils are attracted by bacterial products, IL-8, C5a, and LTB4
Describe step 5: Phagocytosis
-Consumption of pathogens or necrotic tissue; phagocytosis is enhanced by opsonins (IgG and C3b)
-Pseudopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes to produce phagolysosomes
-Chediak-Higashi syndrome characterized by impaired phagolysosome formation with increased risk of pyogenic infections
Describe step 6: Destruction of phagocytosed material
-O2-dependent killing is the most effective mechanism
-HOCl radical generated by oxidative burst in phagolysosomes destroys phagocytosed microbes:
*O2–>O2 radical (superoxide) by NADPH oxidase (oxidative burst)
*Superoxide–> H2O2 (hydrogen peroxide) by superoxide dismutase
*H2O2–>HOCl radical (bleach) by myeloperoxidase (MPO) which is contained in the azurophilic granules (lysosomes) of PMNs
When thinking about step 6 (destruction of phagocytosed material), describe how this happens
-Chronic granulomatous disease is characterized by poor O2-dependent killing
*Due to inherited NADPH oxidase defect
*Leads to recurrent infection and granuloma formation
-O2-independent killing is less effecting than O2-dependent killing and occurs via enzymes present in leukocyte secondary granules
Describe step 7: Resolution
Neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus
Describe serous inflammation
-Due to burn or viral infection, tend to be watery
-Fluid in a serous cavity = effusion
Describe purulent or suppurative inflammation
-Common in bacterial infections
-Thick and yellow (rich in neutrophils). Neutrophils, necrotic cells and serum = “pus”. Abscess = focal collection of pus
Describe fibrinous inflammation
-Rich in fibrin which makes it sticky. Covering called a “pseudomembrane”
-Noted when inflammation occurs in a body cavity (meninges, pericardium and pleura). Can resolve but if scarring occurs could restrict function
-Orally we see a psuedomembrane
What is an ulcer?
Complete loss of surface epithelium due to sloughed (shedding) of necrotic tissue
Where are the common locations for ulceration?
-Mucosal surfaces (mouth, stomach, intestines and genitourinary tract)
-Subcutaneous tissue of the legs/feet in patients with circulatory problems predisposing to extensive necrosis (ex. diabetes, peripheral vascular disease)
Where are eosinophils found?
In inflammatory sites around parasitic infections and associated with IgE mediated immune reactions (allergies)
Eosinophils are recruited by _______
a specific chemokine (eotaxin)
Eosinophilic granules contain _________ which is toxic to parasites and causes epithelial cell necrosis
major basic protein
What is granulomatous inflammation?
A type of chronic inflammation that usually occurs when a material is difficult to digest/remove
When talking about granulomatous inflammation, there are characteristics of specific disease states that arise in 4 main settings. List these 4 settings.
- Persistent T cell response to microbes (myobacteria tuberculosis, T. pallidum, fungi)
- Immune-mediated inflammatory diseases (Crohn disease)
- Sarcoidosis - unknown cause
- Foreign body (suture, silicone, beryllium, prophy paste)
With granulomatous inflammation, the granuloma will wall off the agent, but what happens if the body can’t remove it?
Leads to fibrosis and organ dysfunction
What does Granulomatous Inflammation look like histologically?
Large “epithelioid” (looks like a squamous cell) macrophages/histiocytes that sometimes fuse to form multinucleated giant cells are combined with lymphocytes into structures called a granuloma
With granulomatous inflammation, if it has an accellular/necrotic, cheesy center (caseous necrosis) in the center of the granuloma = caseating or necrotizing granulomatous inflammation. What diseases is this seen in?
Tuberculosis, syphilis, cat-scratch disease
With granulomatous inflammation, if this cheesy center is absent = non-caseating or non-necrotizing granulomatous inflammation. What diseases is this seen in?
Crohn disease, sarcoidosis, foreign body reactions
List the systemic effects of inflammation
Fever
Lymphadenopathy
Leukocytosis
What causes fever in inflammation?
Pyrogens (fever-producing substances - TNF, IL-1, PGE2) acting on the hypothalamus. Unknown purpose for fever
What is Lymphadenopathy?
Firm, enlarged, tender
What is Leukocytosis?
Elevated serum levels of leukocytes:
-Produced in bone marrow, mostly PMNs
-Most bacterial infections increase PMNs
-Some viral infections increase lymphocytes
-Asthma, hay fever, parasitic infections increase eosinophils
-Some organisms can decrease white cell count
What are the systemic effects of acute phase proteins?
-Elevated acute phase proteins are made in liver
-Cause increased HR, BP, chills, rigors (shivering), anorexia, somnolence, malaise
-Can track (in the blood) to see if inflammation is resolving
List some types of Acute Phase Proteins
-C-reactive protein
-Fibrinogen- binds to RBCs, forms stacks that sediment- causes increased erythrocyte sedimentation rate (ESR)
-Serum amyloid A (SAA) protein
What is leukocyte-induced tissue injury?
Damage that occurs when leukocyte enzymes are released into the host tissue
What chronic diseases does leukocyte-induced tissue injury occur?
-Gout
-Rheumatoid arthritis
-Atherosclerosis
-Periodontitis
