Robbins Ch 3: Inflammation and Repair Flashcards
what are three major components of acute inflammation (AI)
- dilation of small vessels
- increased permeability of microvasculature
- emigration of leukocytes to site of injury
Define exudate and when is it commonly seen?
The escape of fluid, proteins, and blood cells from vascular system into interstitial tissue or body cavities. Commonly seen in site of inflammation.
what is a transudate?
Escape of fluid with low protein content, little or no cellular material, and low specific gravity.
_ results from osmotic or hydrostatic imbalance across vessel wall w/o an increase in vascular permeability.
transudate
Edema results from exudate, transudate or both?
Both
Is pus a transudate or an exudate?
exudate
The changes in vascular flow and caliber as seen during acute inflammation, Vasodilation is mediated by _
histamine, prostaglandins, platelet-activating factor, kinins. But the MAIN player is histamine.
List the following vascular changes and caliber as seen in AI in order:
- Vasodilation
- Vascular permeability
- Stasis
- Leukocyte accumulation
1 –>2 –> 3–>4
Increased vascular permeability is a hallmark of acute inflammation. which vessels are these changes seen in?
Postcapillary venules.
Explain the mechanism via which vascular permeability take place.
- Contraction of endothelial ells resulting in increased interendothelial spaces.
- Endothelial injury, resulting in endothelial cell necrosis and detachment
- Increased transport of fluids and proteins (transcytosis) through the endothelial cell.
What causes the immediate transient response as seen in vascular permeability?
Histamine, bradykinin, leukotrienes and other
What are the mediators of vascular permeability?
Histamine, bradykinin, leukotrienes, and other
Give an example where you’d likely to see delayed prolonged leakage as a sign of acute inflammation.
sun burns.
Give an example of a factor that can cause transcytosis as seen in vascular permeability.
VEGF
List few changes seen in lymphatic vessels, and flow that accompanies AI.
- lymph flow is increased and helps drain edema fluid that accumulates becuase of increased vascular permeability.
- lymphatic vessels proliferate during inflammation
- lymphatic can become secondarily inflamed (lymphagitis)
What is reactive lymphadenitis?
Inflamed lymph nodes and enlargement due to hyperplasia of the lymphoid follicles and increased number of lymphocytes and macrophages.
A patient presents to clinic after an appendectomy. The physician notes red streaks near the skin of the incision. What do the streaks indicate?
Infection. The streaking follows the course of the lymphatic channels and is diagnostic of lymphangitis.
As seen during margination, how does the vascular shear stress change?
Wall shear stress decreases allowing for more leukocytes to assume peripheral position.
What two major family of molecules are involved in leukocyte adhesion and migration?
Selectins and integrins
What molecules mediates the initial rolling interactions as seen in leukocyte recruitment to site of injury and what are their ligands?
selectins (E, L, and P). Their ligands are sialylated oligosaccharides bound to mucin-like glycoprotein backbones.
What cytokines mediates the expression of selectin and their ligands?
Cytokines like NTF, IL1 and chemokines.
What two cytokines specifically induces expression of adhesion molecules on endothelial cells of postcapillary venules adjacent to the injury?
TNF and IL-1
Where are P-selectins stored and what mediates their redistribution from storage to cell surface?
They are stored in Weibel-Palade bodies in endothelial cell granules. Histamine and thrombin stimulates their redistribution to cell surface.
Leukocytes express which selectin and ligands for what selectins?
Expresses L-selectin, and expresses ligands for E and P selectins
What cytokines induce expression of ligands for integrins on endothelial cells?
TNF and IL1 mainly
TNF and IL induce endothelial expression mainly of what ligand for integrin?
VCAM1 - the ligand for beta1 integrin VLA-4
ICAM-1 ligand for beta 2 integrins ILFA 1 and Mac1.
How the integrins VLA-4 and LFA1 get converted from low affinity to high affinity?
Leukocytes normally express integrins in low affinity state. chemokines that were produced at the site of injury bind to endothelial cell proteoglycans and are displayed at high concentrations on endothelial surface. these chemokines bind to and activate the rolling leukocytes which converts VLa4 and FLA1 to high affinity state.
What adhesion molecules present in theintercellular junction between endothelial cells are involved in the migration of leukocytes?
PECAM-1.
What is the most common exogenous chemoattract for Leukocytes?
bacterial products, including peptides that possess an N-formylmethionine terminal amino acid and some lipids
what are some common endogenous chemoattract for leukocytes?
- cytokines like IL-8
- components of complement system, mainly C5a
- Arachidonic acid metabolites mainly Leukotriene B4 (LTB4)
In chemotaxis of leukocytes, leukocyte moves by extending _
filopodia
What are some phagocytic receptors that are used to attach to particle to be ingested by leukocyte/
- mannose receptors
-scavenger receptors
receptors various opsonins
Explain how the macrophage mannose receptor is able to bind only to microbes and not mammalian cells.
Macrophage manose receptor is able to bind terminal mannose and fructose residues of glycoproteins and glycolipids. these sugars are typically part of molecules found on microbial cell walls. Mammalian glycoproteins and glycolipids has sialic acid or N-acetylgalactosamine.
What do scavenger receptors bind?
Originally thought to find LDL that can no longer bind to it’s own receptors, but can bind to variety of microbes.
Name a macrophage integrin that binds microbes for phagocytosis
Mac-1 (CD11b/ CD18)
What are some common opsonins that facilitate recognition by phagocytes
- IgG antibodies
- C3b
- Plasma lectin notably mannose-binding lectin
_ system is considered the most efficient bactericidal system of neutrophils
H202-MPO-halide
H202 cannot kill on it’s own, what enzyme found in neutrophils make it a potent killer by combining with a halide?
myeloperoxidase
How does peroxynitrite kill microbes?
Attacks and damage lipid proteins and nucleic acids
Which neutrophil granules contains myeloperoxidase?
Primary granule (aka larger azurophils)
Which lymphocytes has a role in acute inflammation and the absence of which prones individuals to infections by fungi and bacteria?
TH17 which produces IL17
What molecules (factors, cytokines etc) are known to inhibit /terminate inflammation?
- Lipoxins
- TGF-beta
- IL-10
What is the source of histamine and what are its actions?
Source: mast cells, basophils, platelets
Action: vasodilation, increased vascular permeability, endothelial activation
What are the sources of prostaglandins and what are its actions?
Source: mast cells, leukocytes
Action; Vasodilatio; pain, fever
What are the sources of Leukoctrienes and what are its actions?
Source: mast cells, leukocytes
Actions: increased vascular permeability, chemotaxis, leukocyte adhesion, and activation
Cytokines (TNF, IL-1, IL-6), source and action
Source: macrophages, endothelial cells; mast cells
Actions: Local: endothelial activation. Systemic: fever, metabolic abnormalities, hypotension
What are the sources and action of chemokines?
Source: leukocytes, activated macrophages
Action; chemotaxis, leukocyte activation
What are the sources and actions of platelet-activating factor?
Source: Leukocytes, mast cells
Action; vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
what are the sources and actions of comlements?
Source: liver
Action: leukocyte chemotaxis and activation, direct target killing (MAC), vasodilation
what are sources and action of kinins?
Source: Plasma (liver)
Action; increased vascular permeability, smooth muscle contraction, vasodilation, pain
What are the stimuli for histamine release?
- physical injury
- binding of ab to mast cells
- products of complement called anaphylatoxins (C3a, C5a)
- neuropeptides (substance P)
- cytokines (IL1, IL8)
Histamine has it’s effects by binding to what receptor?
H1 receptor
Mechnical, chemical, and physical stimuli or other mediators release AA from membrane phospholipids through the action of what enzyme?
phospholipase, particularly phospholipase A2.
Which leukotrienes are involved in bronchospasm and increased vascular permeability?
Leukotriene C4, D4, and E4.
Which prostaglandins cause vasodilation and vascular permeability?
PGD2 and PGE2.
which prostaglandins cause vasodilation and also inhibits platelet aggregation?
PGI2.
Which cyclooxygenase is constitutively expressed in most tissues, where it serve a homeostatic function in fluid and electrolyte balance in kidneys, cytoprotection in GI.
COX-1
which prostaglandins causes uterine contraction and bronchial smooth muscle and small arterioles?
PGF2a
Which prostaglandin is hyperalgesic and makes the skin hypersensitive to painful stimuli such as intradermal injection of suboptimal concentrations of histamine and bradykinin?
PGE2
Leukotrienes are produced by the action of what enzyme?
lipoxigenase
What are the sources of TNF and what is their action in inflammation?
Source: macrophages, mast cells, T lymphocytes
Action: stimulates expression of endothelial adhesion molecules and secretion of other cytokines; systemic effect
What is the source and action of IL-1
Source: macrophage, endothelial cells, some epithelial cells
Action: similar to TNF; greater role in fever
What is the source and action of IL6
Source: macrophages and other
Action: systemic effects (acute phase response)
What is the source and action of IL17
Source: T lymphocytes
Action; recruitment of neutrophils and monocytes
IL-8 fall into this class of chemokines where one amino acid residue separates the first of the four conserved cysteine residues.
C-X-C chemokines
This class of chemokines includes MCP1, eotaxin, MIP-1a, and RANTES.
C-C chemokines
Fractalkine belongs to this class of chemokines.
CX3C
Chemokines have their action via binding to what kind of receptors?
G protein-coupled receptors
The critical step of the complement system activation is _ and occurs via what three pathways?
C3.
Occurs via: 1. classical pathway -triggered by fixation of C1 to Ab (IgM or IgG) ; 2. alternative pathway -triggered by microbial surface molecules; 3. lectin pathway - plasma mannose-binding lectin binds to carb on microbes and directly activates C1
In the complement system activation explain the pathway after C3 is activated.
C3 splits into C3a and C3b. C3a is released and plays a role in anaphylaxis. C3b remains attached to cell and then binds to previously generated fragments to form C5 convertase which cleaves C5 to release C5a and leave C5b attached to the cell surface. C5b binds the late components of C6-C9 to form MAC
Which complement cleavage product is chemoattractant for neutrophils, monocytes, eosinophils, and basophils?
C5a
Which complement cleavage product is able to activate the lipoxygenase pathway of AA metabolism?
C5a.
Which complement cleavage product is able to opsonize and help with phagocytosis?
C3b
Cell lysis by complement works best for what kind of bacteria?
bacteria with thin cell wall like Neisseria
Hereditary angiodema is due to inherited deficiency in _.
C1 INH (C1 inhibitor)
Decay accelerating factor (DAF) and CD59 and linked to plasma membrane by _. DAF prevents the formation of _ convertase; CD59 inhibits formation of _.
glycophosphatidyl (GPI) anchor. DAF prevents C3 convertase formation
CD59 inhibits formation of MAC
In paroxysmal nocturnal hemoglobinuria (PNH), due to deficiency of _.
glycophosphatidyl (GPI) anchor.
What is the PAF and it’s function?
phospholipid-derived mediator that causes platelet aggregation, but also is known to vasoconstriction and bronchoconstriction, at low concentration it induces vasodilation and increased venular permeability.
Describe how bradykinin is produced?
Kallikrein cleaves the plasma glycoprotein kininogen
what is the function of bradykinin
Increase vascular permeability and causes contraction of smooth muscle, dilation of blood vessel, and pain when injected into the skin
What is the role of Neuropeptides
Secreted by sensory nerves and leukocytes, and may play a role in initiation and regulation of inflammatory responses.
How des serous inflammation appear morphologically?
Exudation of cell-poor fluid into spaces created by cell injury or into body cavities. e.g. pleural effusion, skin blister
Fibrinous exudate develops due to_
Occurs when vascular leaks are large or when there is a local procoagulant stimulus. Characterized by inflammation in the lining of body cavities such meninges, pericardium and pleura
What happens when fibrous exudates is not dissolved by fibrinolysis and cleared by macrophages?
It will stimulate the ingrowth of fibroblasts and blood vessels and lead to scurring
How is purulent (suppurative) inflammation characterized?
production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid.
What is the most frequent cause of purulent inflammation?
Infection with bacteria that cause liquefactive tissue necrosis like staphylococci (pyogenic bacteria)
Define what an ulcer is.
Local defect or excavation, of surface of an organ or tissue that produced by the sloughing (shedding) of inflamed necrotic tissue.
In terms of inflammation resolution, what is meant by organization?
Growth of connective tissue into the area of damage or exudate converting it into a mass of fibrous tissue.
Morphologically, what are three common features of chronic inflammation?
- infiltration with mononuclear cells
- Tissue destruction
- Attempts at healing
What induces the classical macrophages activation.
Induced by microbial products such as endotoxin, which engage TLRs and other sensors; by T cell-derived signal, importantly the cytokine IFN-y.
Once activated, classical macrophages produce what products?
NO, ROS, and upregulate lysosomal enzymes.
What induces macrophages in the alternative pathway?
Cytokines other than IFN-y, such as IL-4 and IL-13
What is the major role of M2 form of macrophages?
Tissue repair
CD4 T lymphocytes have the ability to promote inflammation producing/secreting what products?
TH1 produce cytokine IFN-y which activate macrophages by classical pathway
TH2 secrete IL-4, IL-5, and IL-13 which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation.
Defense against helminthic parasites and allergic inflammation is provided by which T cells?
TH2
Which T cells plays a role in autoimmune diseases
TH1
Explain how Lymphocytes and macrophages interact in a directional way which play a role in propagating chronic inflammation.
Macrophages display antigens to T cells, express membrane molecules (costimulators), and produce cytokines (L12 and others) stimulate T cells responses. Activated T cells in turn produce cytokines which recruit and activate macrophages, promoting more antigen presentation cytokine secretion.
what are tertiary lymphoid organs?
In some chronic inflammatory reactions, the accumulated lymphocytes, antigen presenting cells, and plasma cells cluster together to form lymphoid tissues resembling lymph nodes.
_ is a highly cationic protein that is toxic to parasites but also cause lysis of mammalian epithelial cells.
Major basic protein
Presence of what characterizes granulomatous inflammation?
Collection of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis.
Presence of epitheliod cells and giant cells are often seen in what kind of inflammation?
Granulomatous inflammation.
What are characteristics of foreign body granulomas?
- incited by inert foreign bodies like talc
- absence of T cell-mediated immune responses
- do not incite any specific inflammatory or immune response
What are some characteristics of immune granulomas?
- inducing a persistent T-cell mediated immune response
- inciting agent is a difficult to eradicate like persistent microbe or self antigen.
What are the three major acute-phase-proteins?
- CRP
- fibrinogen
- serum amyloid A (SAA)
What cytokine stimulates production of CRP and fibrinogen?
IL-6
which cytokines stimulates SAA
IL-1 and TNF
In hepatic regeneration, what cytokines is involved in the priming phase?
IL-6
In priming the phase of hepatic regeneration, what cells make IL-6 and where do act?
Made by Kupffer cells and act on hepatocytes.
In the growth phase of hepatic regeneration, what growth factors are involved?
HGF and TGF-a and helps the hepatocyte to enter the cell cycle.
what are the steps involved in angiogenesis?
- vasodilation in response to nitric oxide and increased permeability induced by vasular endothelial growth factor (VEGF)
- separation of pericytes from abluminal surface and breakdown of the basement memrbane to allow formation of a vessels sprout
- migration of endothelial cells toward the area of tissue injury
- proliferation of endothelial cells just behind th eleading front tip of migrating cells
- remodeling into capilllary tubes
- recruitment of periendothelial cells
- suppression of endothelial proliferation and migration and deposition of the basement membrane
In Angiogenesis, VEGF-A promotes vasodilation by stimulating the production of _ and contributes tot he formation of the vascular lumen.
NO
_ stimulates the proliferation of endothelial cells in angiogenesis.
FGF-2
_ interacts with a tyrosine kinase receptor on endothelial cells called Tie2
Ang1
In angiogenesis, what role does PDGF and TGF-beta play?
PDGF = recruits smooth muscle a cells TGF-beta= suppresses endothelial proliferation and migration, and enhances the production of ECM proteins.
Through cross-talk with VEGF, the _ signaling pathway regulates the sprouting and branching of new vessels and thus ensures that new vessels that are formed have the proper spacing to effectively supply the healing tissue with blood.
Notch
In the deposition of connective tissue, _, _ and _ are growth factors produced by _.
PDGF, FGF-2, and TGF-beta, produced by macrophages.
In deposition of connective tissue, _ stimulates fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased degradation of ECM due to inhibition of MMP.
TGF-beta
what cells are responsible for the contraction of scar over time?
myofibroblasts
In remodeling of connective tissue, MMP’s which cleave fibrillar collagen include _
MMP1, 2, and 3)
Gelatinases, aka MMP2 and 9 is responsible for degrading _
amorphous collagen and fibronectin
Stromylysin aka MMP3 10 and 11 are responsible for degrading _
variety of ECM constituents including proteoglycans, laminin, fibronectin, and amorphous collagen
Activated collagenases can be inhibited by _
TIMPs
ADAM, a family of enzymes related to MMP’s cleaves and releases what cytokines/growth factor?
TNF, TGF-beta and EGF.
In healing by first intention, within 24 hours of an injury, what cells are seen at the incision margin, migrating toward the fibrin clot?
Neutrophils
in healing by first intention, by what day are you likely to see neovascularization reaching its peak as granulation tissue fills the incisional space?
Day 5
In healing by first intention, migration of fibroblasts to the site of injury is driven by what ?
chemokines, TNF, PDGF, TGF-ebta, and FGF
In healing by second intention, at first provisioinal matrix containing fibrin, plasma fibronectin, and type III collagen is formed, but in about 2 weeks this is replacecd by a matrix composed mainly of what collagen?
Collagen type I.
