Lecture 3: Inflammation and Repair Flashcards
Asthma (chronic and acute) is due to what immune cells?
Eosinophils, IgE Abs
Glomerulonephritis is due to what cells?
Acute or chronic?
- Abs and complement, neutrophils, monocytes
- Acute
Septic shock is due to what cells?
Acute or chronic?
- Cytokines (cytokine storm)
- Acute
Arthritis is due to what cells?
Acute or chronic?
- Lymphocytes, macrophages
- Chronic
Atherosclerosis is due to what cells?
Acute or chronic?
- Macrophages, lymphocytes
- Chronic
Pulmonary fibrosis is due to what cells?
Acute or chronic?
- Macrophages, fibroblasts
- Chronic
What kind of inflammation is characterized by the following: mostly neutrophils, prominent local and systemic signs, mild and self-limited tissue injury, fibrosis.
Acute inflammation
Primary granules (azuorphilic) of neutrophils contain what?
How are they described?
- MPO, bactericidal factors (lysozyme, defensins), acid hydrolases, and variety of neutral proteases (elastase, cathepsin G, non-specific collagenases, proteinase 3)
- Larger
Secondary (specific) granules of neutrophils contain what?
Described as what?
- Lysoszyme, collagenase, gelatinase, lactoferrin, histaminase, and alkalne phosphatase
- Smaller
Cells express receptors in what 3 places which allows them to sense the presence of foreign invaders in any cellular compartment?
- Plasma membrane for extracellular microbes
- Endosome for ingested microbes
- Cytosol for intracellular microbes
Sensors of cell damage can detect what molecules?
- Uric acid (DNA breakdown)
- ATP (damaged mitochondria)
- Reduced intracellular K+ (loss of plasma membrane integrity)
- DNA
Gain of function mutations in the sensors for cell damage cause rare diseases known as _______ and they are treated with _________.
Gain of function mutations in the sensors for cell damage cause rare diseases known as autoinflammatory syndromes and they are treated with IL-1 antagonists.
What are the 3 major components of acute inflammation?
1) Dilation of small vessels leading to an increase in blood flow
2) Increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave circulation
3) Emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and activation to eliminate the offending agent
Escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as?
What is found in high concentrations in this fluid?
Inflammatory or non-inflammatory edema?
- Exudation = inflammatory edema
- High protein
A fluid with low protein content (most of which is albumin) with no to little cellular debris and low specific gravity - essentially an ultrafiltrate of blood is known as?
Inflammatory or non-inflammatory?
Produced as a result of?
Examples of disease?
- Transudate = non-inflammatory ededma
- Osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability
- CHF increases hydrostatic pressure due to venous outflow obstruction
- Liver disease causing decreased protein synthesis or kidney disease causing increased protein loss = decreased colloid osmotic pressure
What is the source of histamine?
Action?
- Mast cells, basophils, platelets
- Vasodilation, increased vascular permeability, and endothelial activation
The increased vascular permeability seen with acute inflammation happens where specifically?
Post-capillary venules
*Hallmark of acute inflammation
Inflamed lymph nodes are often enlarged because of ______ of the lymphoid follicles and increased number of lymphocytes and macrophages
Hyperplasia
Blood flow slows early in inflammation (stasis), hemodynamic conditions change (wall shear stress decreases), and more white cells assume a peripheral position along the endothelial surface. This process of leukocyte redistribution is called?
Margination
Tissue macrophages, mast cells, and endothelial cells that encounter microbes and dead tissue secrete which cytokines that act on the endothelial cells of post-capillary venules adjacent to an infection?
Which selectin and ligand are expressed first?
- IL-1 and TNF
- E-selectin
- Ligand for L-selectin
Histamine and thrombin stimulate the redistribution of __-selectin from its normal intracellular stores in endothelial cell granules called?
- P-selectin
- Weibel-Palade bodies
*Mnemonic: Weibel-Palade == W-P == vWF and P-selectin
Red streaks near a wound is a telltale sign of?
Streaking follows the course of the lymphatic channels and is diagnostic of; may be accompanied by painful enlargement of draining lymph nodes, indicating?
- Sign of infection in the wound
- Lymphangitis: inflammation of lymph vessels (red-streaks)
- Lymphadenitis: inflamed, often enlarged lymph nodes (lymphadenapothy)
What integrins are converted into a high-affinity state upon activation of the cell?
VLA-4 and LFA-1 on the leukocytes
What is the source of PGs?
Action?
- Mast cells, leukocytes
- Vasodilation, pain, fever
IL-1 and TNF induce endothelial expression of ligands for integrins, what are the 2 main ligands and their corresponding integrins on the leukocytes?
- VCAM-1 (CD106), the ligand for β1 integrin VLA-4
- ICAM-1 (CD54), the ligand for β2 integrin LFA-1 and Mac-1
What are the ligands for the selectins?
Sialylated oligosaccharides bound to mucin-like glycoprotein backbones (Sialyl-Lewis X)
What is the adhesion molecule present in the intercellular junctions between endothelial cells that’s part of the Ig superfamily, where is it found and what is its ligand?
- CD 31 (PECAM-1)
- Endothelial cells AND leukocytes
- Ligand = CD31 (PECAM-1) = homotypic interaction
What is the most common exogenous chemoattractant and the endogenous chemoattractants?
Exogenous: N-formylmethionine
Endogenous: IL-8, C5a, Arachidonic acid metabolites, mainly LTB4
Chemoattractant agents bind to what kind of receptors on leukocytes?
Activate which second messengers?
Leads to which reorganization?
- GPCRs
- Rac/Rho/cdc42 family (guanosine triphosphates), increase Ca2+
- Leads to reorganization of the cytoskeleton
Which leukocyte infiltrate predominates early in the response (6-24 hours) and later in the response (24-48 hours)
- Neutrophils are first and short-lived
- Monocytes are dominant in prolonged inflammatory rxns
What is the predominant leukocyte in Pseudomonas bacterial infections?
- Neutrophils dominate
- Will be continously recruited (exception)
Hypersensitivity reactions are dominated by which immune cells?
Activated lymphocytes, macrophages, and plasma cells
Agents that block _____ are among the most sucessful therapeutics ever developed for chronic inflammatory diseases?
TNF
*One of the major cytokines in leukocyte recruitment
What is the source of LTs?
Action?
- Mast cells, leukocytes
- Inc vascular permeability, chemotaxis, leukocyte adhesion and activation
What is the source of PAF?
Action?
- Leukocytes, mast cells
- Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, oxidative burst, de-granulation
What is the source of kinins?
Action?
- Plasma (made in liver)
- Increased vascular permeability, smooth muscle contraction, vasodilation, pain
What PGs or LTs are responsible for vasodilation?
PGI2 (prostacyclin), PGE1, PGE2, and PGD2
What PGs or LTs are responsible for vasoconstriction?
TxA2, LTC4, LTD4, LTE4
What PGs or LTs are responsible for increased vascular permeability?
LTC4, LTD4, LTE4
What PGs or LTs are responsible for chemotaxis and leukocyte adhesion?
LTB4, HETE
What PGs or LTs are responsible for bronchospasm (important in asthma), intense vasoconstriction, and increased permeability of venules?
LTC4, LTD4, LTE4
ROS are produced by the rapid assembly and activation of a multicomponent oxidase called?
Produces what?
- NADPH oxidase
- O2-* (superoxide anion)
In the respiratory burst within lysosomes and phagolysosome what are the series of rxns and the ROS produced?
How does the final product destroy microbes?
O2—(NADPH ox)—> O2-*–(SOD)—> H2O2 –(MPO)—> HOCl- (bleach)
- Destroys microbes through halogenation or by oxidation of proteins and lipids (lipid peroxidatio)
What are the 5 anti-oxidant mechanisms to combat ROS produced during the killing of microbes and protect the host?
1) SOD
2) Catalase: detoxifies H2O2
3) Glutathione peroxidase: detoxifies H2O2
4) Ceruloplasmin
5) Iron-free fraction of serum transferrin
Nitric oxide (NO) is produced by NOS, of which there are 3 different types, what are they?
How/when is each expressed?
- eNOS (endothelial-vascular tone) and nNOS (neuronal-NT) are constitutively expressed at low levels
- iNOS (inducible) kills microbes and induced by IFN-y or microbial products
NO reacts with what to produce what ROS that attacks lipids, proteins, and nuclei acids of microbes and host cells?
NO reacts with superoxide anion to makes ONOO
Lysosomal enzymes, if not controlled, can damage the host. Which antiproteases in the serum and tissue fluids serve as protection?
Major inhibitor of?
- α1-antitrypsin is major inhibitor of neutrophil elastase
- α2-macroglobulin
What is the function of major basic protein?
Cationic protein of eosinophils, that is cytotoxic to many parasites
Viscous meshwork of nuclear chromatin that binds and concentrates granule proteins such as antimicrobial peptides and enzymes is known as?
Neutrophil Extracellular Trap (NET)
The nuclear chromatin in the NETs, which includes histones and associated DNA, has been postulated to be a source of nuclear antigens in which diseases?
Systemic autoimmune diseases, particularly lupus
Which T lymphocytes play an important role in acute inflammation?
What do they produce?
Deficiency produces; increased susceptibility to?
- TH17 cells
- Produce IL-17, which induces secretion of chemokines that recruit leukocytes
- Deficiency = cold abscesses = more susceptible to bacterial and fungal infections
What is the source of Cytokines (TNF, IL-1, IL-6)?
Actions (both local and systemic)?
- Macrophages, endothelial cells, mast cells
Local: endothelial activation (expression of adhesion molecules)
Systemic: fever, metabolic abnormalities, hypotension (shock)
During termination of the acute inflammatory response which anti-inflammatory cytokines are released?
TGF-β and IL-10
Where is serotonin is found as a preformed vasoactive mediator where?
Primary function?
Effect on vasculature?
- Platelets and certain neuroendocrine cells in GI tract
- Primary function = NT in the GI tract
- Also a vasoconstrictor
What causes release of arachidonic acid from membrane phospholipids?
Phospholipase, mainly phospholipase A2
What biochemical signals activate phospholipase A2?
Increase in cytoplasmic Ca2+ and other kinases in response to external stimuli
What synthesizes eicosanoids (20-carbon fatty acids)?
Why are eicosanoids considered dynamic?
- Cyclooxygenases and lipooxygenases
- Bind GPCRs on many cell types and can mediate virtually every step of inflammation
What inhibits phospholipases?
Steroids
Prostaglandins are derived from where and via what enzyme?
Arachidonic acid via Cyclooxygenase
What is an inhibitor of inflammation arising from arachidonic acid?
What enzyme makes these?
- LXA4 and LXB4
- 12-lipoxygenase
What are the 3 key mediators of chronic inflammation?
- IL-12
- IFN-gamma
- IL-17
COX-1 and COX-2 are stimulated by?
Where is each expressed?
Functions of each?
- Stimulated by inflammation
- COX-1 constitutively expressed in most tissues; fluid/electrolyte balance kidneys, cytoprotection in the GI tract
- COX-2 is low or absent in most tissues; generates the prostaglandins involved in inflammatory response
What are COX-1/2 inhibitors?
- Aspirin and NSAIDs
- Inhibit prostaglandin synthesis
What is the precursor for leukotrienes?
Produced by what enzyme?
Action?
- 5-hydroxyeicosatetraenoic acid from 5-lipoxygenase
- Chemoattractant for neutrophils
Lipoxins are generated from arachidonic acid but have a different effect than do prostaglandins and leukotrienes, which is?
Inhibit neutrophil chemotaxis and adhesion to endothelium
Why might selective COX-2 inhibitors increase the risk of cardiovascular and cerebrovascular events?
- They impair endothelial production of PGI2, a vasodilator and inhibitor of platelet aggregation
- Leaving intact COX-1 mediated production by platelets of thromboxane A2, an important mediator of platelet aggregation and vasoconstriction
5-lipoxygenase is not affected by NSAIDs, and many new inhibitors of this pathway have been developed, such as Zileuton. What does this drug inhibit and is useful in treatment of?
- Inhibits leukotriene production
- Useful in tx of asthma
Corticosteroids are broad-spctrum anti-inflammatory agents that reduce trasncription of genes encoding?
COX-2, phospholipase A2, pro-inflammatory cytokines (IL-1 and TNF), and iNOS
Why is increasing consumption of fish oil effective in manipulating inflammatory responses?
- Polyunsaturated FA’s in fish oil are poor substrates for conversion to active metabolites by the COX and lipoxygenase pathways
- Better substrates for the production of anti-inflammatory lipid products
What are the 5 cytokines involved in acute inflammation?
1) TNF
2) IL-1
3) IL-6
4) Chemokines
5) IL-17
What is the source of IL-12?
Action in inflammation?
- DC, macrophages
- Increased production of IFN-gamma
What is the source of IFN-gamma?
Action in inflammation?
- T lymphocytes, NK cells
- Activation of macrophages
What is the source of IL-17?
Action in inflammation?
- T lymphocytes
- Recruitment of neutrophils and monocytes
What is the source of TNF?
Action in inflammation?
- Macrophages, mast cells, T lymphocytes
- Stimulates expression of endothelial adhesion molecules and secretion of other cytokines
What is the source of IL-1?
Action in inflammation?
- Macrophages, endothelial cells
- Similar to TNF, but greater role in fever
What is the source of IL-6?
Action in inflammation?
- Macrophages, other cells
- Acute phase response
Complement system is a collection of what kind of proteins?
Soluble proteins in the plasma
The critical step of complement activation is the proteolysis of which component?
Occurs via what 3 pathways?
- C3
- Classical, alternative, or lectin pathways
All 3 pathways of complement activation lead to the formation of which active enzyme?
What are its products?
- C3 convertase
- Splits C3 into C3a and C3b
Increased vascular permeability, contraction of smooth muscle, dilation of blood vessels, pain when injected into skin are all properties of?
Bradykinin
Suppurative or liquefactive necrosis indicates what kind of infection?
Bacterial infection (staphylococci = pyogenic = pus-producing)
The classical pathway is triggered by (hint: there is a mnemonic)?
C1 binding to IgM or IgG that has already combined with an Ag
*GM makes Classic cars*
Inherited deficiency of this factor leads to hereditary angioedema?
C1 inhibitor
Which 2 proteins are linked to plasma membrane by a GPI anchor and play a role in inhibiting complement?
What does each inhibit?
Acquired deficiency of enzyme that creates GPI anchors leads to?
Decay Accelerating Factor (DAF): prevents formation of the C3 convertase
CD59: prevents formation of the Membrane Attack Complex (MAC)
- Deficiency of these regulators = excessvie complement activation and lysis of red cells = paroxysmal nocturnal hemoglobinuria (PNH)
What is a common example of acute suppurative inflammation?
Acute appendicitis
Infiltration by what cells typify chronic inflammation?
Macrophages
Lymphocytes
Plasma cells
What activates M1 (classical) macrophages?
Microbes (endotoxin/TLR) and INF-gamma
M1 Macrophages secrete what cytokines that will increase inflammation?
IL-1, IL-12, IL-23
M1 macrophages can perform phagocytosis, via what mediators?
ROS, NO, lysosomal enzymes
What activates M2 Macrophages?
IL-4 and IL-13
M2 macrophages secrete what cytokines for tissue repair and fibrosis?
Anti-inflammatory effects?
- GFs and TGF-β = tissue repair and fibrosis
- IL-10 and TGF-β = anti-inflammatory effects
What type of CD4 cells is responsible for defense against extracellular bacteria and fungi?
Secretes what cytokines?
- TH17
- IL-17, IL-22
What are the 3 subsets of CD4+ T cells?
What cytokines do they secrete?
Function?
1) TH1 cells; IFN-y; activate M1 macrophages
2) TH2 cells; IL-4, IL-5, IL-13; recruit and activate eosinophils and activation of M2 macrophages
3) TH17 cells; IL-17 and other cytokines; induce secretion of chemokines responsile for recruiting neutrophils (and monocytes) into rxn
Which CD4+ subsets are involved in defense against many types of bacteria and viruses and in autoimmune diseases?
TH1 and TH17 cells
Which CD4+ subset is important in defense against helminthic parasites and in allergic inflammation?
TH2 cells
Granulomatous inflammation is a form of chronic inflammation characterized by what type of cells?
Sometimes associated with what?
- Activated macrophages and T lymphocytes
- Central necrosis
What are the 4 clinically important acute-phase reactants?
- CRP
- Fibrinogen
- SAA
- Hepcidin
In granulomatous inflammation the activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells, and are called?
Some macrophages fuse forming what?
- Epitheliod cells
- Multinucleate giant cells (AKA Langerhans giant cells)
Foreign body granulomas cause what kind of immune response?
- Do not incite an immune response or inflammation
- Epitheliod and giant cells are apposed to the surface of the foreign body
What causes immune granulomas?
What do macrophages activate and cytokines involved?
- Caused by variety of agents capable of inducing a persistent T cell-mediated immune response
- Macrophages activate T cells to produce cytokines, such as IL-2, which activates other T cells, perpetuating the response, and IFN-y, which activates the macrophages
What is the prototype of a granulomatous disease caused by infection and should always be excluded as the cause when granulomas are identified?
What is the granuloma referred to as in this dease?
- Tuberculosis
- A tubercle
Which cytokines are important mediators of the acute-phase reaction?
- TNF
- IL-1
- IL-6
- Type I interferons
Which prostaglandin in the hypothalamus stimulates the production of NT’s that reset the temperature set point at a higher level to induce fever?
PGE2
FIbrinogen binds to red cells and causes them to form what?
Basis for measuring what as a simple test for an inflammatory response cause by any stimulus?
- Form stacks (rouleaux) that sediment more rapidly at unit gravity
- Erythrocyte sedimentation rate (ESR)
Which cytokines stimulate CRP, fibrinogen, and SAA?
- IL-6 for CRP and fibrinogen
- IL-1 and TNF for SAA
Chronically elevated levels of ______ reduce the availability of iron and are responsible for the anemia associated with chronic inflammation
Hepcidin
Elevated levels of ______ have been proposed as a marker for increased risk of MI in patients with coronary artery disease?
CRP
Bacterial infections are characterized by what cells usually?
Viral?
- Neutrophils (bacterial) = neutrophilia
- Lymphocytes (viral) = lymphocytosis
Extreme elevation of leukocytes are referred to as?
Leukemoid reaction; similar to the white cell count seen in leukemia
Typhoid fever, rickets, or Protozoa results in what condition?
- Leukopenia = decreases white cell count
Leukocytosis occurs initially because of accelerated release of cells from the bone marrow postmitotic reserve pool and is therefore associated with a rise in the number of immature neutrophils in blood, know as what?
Left shift
What is the clinical triad of septic shock?
1) Disseminated intravascular coagulation
2) Hypotensive shock
3) Metabolic disturbances (i.e., insulin resistance and hyperglycemia)
If fibrosis develops in a tissue space occupied by an inflammatory exudate, it is called?
Organization
What are the most important source of growth factors near a site of damage/injury?
Macrophages; epithelial and stromal cells also produce some too
Stable tissues are quiescent in which stage of cell cycle?
Found where?
- G0 stage; have a limited capacity to regenerate, except for the liver
- Parenchyma of most solid tissues, such as liver, kidney, and pancreas; also include enothelial cells, fibroblasts, and smooth muscle cells
Acute respiratory distress syndrome is due to what cells?
Neutrophils
Who said that inflammation is not a disease, but a stereotypic response?
John Hunter
Who established the concept that chemical substances like histamine mediate vascular change in inflammation?
Sir Thomas Lewis
Who discovered phagocytosis via observation of amebocytes?
Ellie Metchnikoff
What mediators are responsible for the immediate transient response?
Histamine, bradykinin, LTs
What occurs during the first, or priming phase of hepatocyte proliferation?
Kupffer cells produce IL-6 which acts on hepatocytes to make parenchymal cells competent to receive and respond to growth signals
What occurs during the second, or growth factor phase in hepatocyte proliferation?
How long does this process take?
- GFs such as HGH and TGF-α act on primed hepatocytes to stimulate cell metabolism and entry of the cells into the cell cycle
- Because they are quiescent cells, takes hepatocytes several hours to enter the cell cycle, progress from G0 to G1 and reach S phase of DNA replication
What occurs during the final or termination phase in hepatocyte proliferation?
Hepatocytes return to quiescence; antiproliferative cytokines of TGF-β family likely involved
In situations where the proliferative capacity of hepatocytes is impairedm such as after chronic liver injury or inflammation, what is the major liver regeneration method?
Regeneration from progenitor cells
What stimulates transcytosis?
What else does it do?
- VEGF
- Promotes vascular leakage
What is the mainly responsible for a creating transudates fluid?
Decreased colloid osmotic pressure (liver disease) or increased protein loss (kidney disease)
During leukocyte rolling, what is expressed on the endothelium to slow down leukocytes?
On the leukocytes themselves?
P-selectin (from Weibel-Palade) bodies and E-selectin
L-selectin and ligands for P and E selectin
What do selectins bind on leukocytes?
Sialyl Lewis X bodies
Leukocyte migration is via what?
Where does it occur?
What is involved?
Transmigration/diapedesis
Postcapillary venules
CD-31/PECAM-1
What kind of infection is dominated by neutrophils for several days as opposed to macrophages?
Pseudomonas bacteria
What is the ligand for ICAM-1, located on monocytes and DCs?
On neutrophils?
- MAC-1
- LFA-1
What are the ligands for VCAM-1, located on T cells?
- VLA-4
- Alpha4-Beta7
What are the major opsonins?
C3b and IgG
What is the phagocytosis dependent on (in regards to actin)?
Polymerization of actin filaments
When is iNOS induced?
What does it catalyze?
- When macrophages and neutrophils are activated by IFN-y or microbial products
- Arginine —> NO
What can cleave C3 and C5 yielding anaphylatoxins?
Neutral proteases
What is the major inhibitor of neutrophil elastase?
α1-antitrypsin
What is stored in preformed molecules and are released 1st during inflammation?
Histamine and serotonin
What activates acute phase proteins from the liver?
IL-1 and IL-6
What cytokines stimulate leukocyte production from the bone marrow?
TNF
IL-1
IL-6
What are C-C chemokines that attract monocytes, eosinophils, basophils, lymphocytes?
MCP-1
Eotaxin
MIP-1a
RANTES
What is the only CX3C chemokines?
What forms?
- Fractalkine
- Cell-surface bound and soluble form with chemoattractant activity
What is responsible for inhibiting viral replication?
Type I IFN
What inhibits MAC formation?
CD59
Serous inflammation is marked by what?
What linings of the body?
Example?
- Exudation of cell-poor fluid into spaces created by cell injury into body cavities lined by
- Peritoneum, pleura, pericardium
- Skin blistering after burn, viral infection
When does a fibrinous exudate develop?
Characteristic of what body cavity linings?
- When vascular leaks are large or there is a local Procoagulant stimulus (cancer cells)
- Meninges, pericardium, and pleura
What bacterial infection is most common in purulent inflammation?
Example?
- Staphylococci
- Appendicitis
What are localized collections of purulent inflammatory tissue?
Produced by what?
- Abscesses
- Seeding of pyogenic bacteria into a tissue
What is a local defect, excavation of the surface of an organ or tissue that is produced by the sloughing of inflamed necrotic tissue?
Ulcer
What is the most common locations of ulcers?
- Mucosa of the mouth, stomach, intestine, genitourinary tract AND
- Skin and subcutaneous tissue of the lower extremities in older people
When does chronic inflammation occur (3 factors)?
- Persistent infection
- Hypersensitivity disease
- Prolonged exposure to toxic agent
What is chronic inflammation characterized by?
- Infiltration of macrophages, lymphocytes, plasma cells
- Tissue destruction
- Attempts at healing
Macrophages in the spleen and LNs are called what?
Sinus histiocytes
In what condition of chronic inflammation may neutrophils be present and dominate?
Osteomyelitis
What comes together to form tertiary lymphoid organs in some chronic inflammatory reactions?
Examples?
- Lymphocytes, APCs, plasma cells
- R.A. And Hashimoto’s
How do you identify a foreign body Granuloma?
Examples?
- Center of Granuloma with polarized light, appears refractile
- Talc, sutures
Activated macrophages in granulomas have what features?
Pink granular cytoplasm with indistinct cell boundaries called epitheloid cells
In what disease/condition is there non-caseating necrosis present with granulomas?
- Chron’s
- Sarcoidosis
- Foreign body reaction
What kind of tissue reaction does Myobacterium leprae cause?
- Acid-fast bacilli in macrophages
- Noncaseating Granuloma
What type of tissue reaction does Treponema pallidum cause?
What disease?
- Gemma, plasma cell infiltrate, no loss of cellular outline
- Syphillis
What causes cat-scratch disease?
Tissue reaction?
- Gram-negative bacillus
- Rounded or stellate Granuloma, giant cells UNCOMMON
Describe the formation of a Granuloma starting with macrophages and ending with epitheloid cells
Macrophages secrete IL-12 -> Th1 -> IFN-gamma -> epitheloid cells
What are the clinical manifestations of the acute phase response?
INC BP and pulse
DEC sweating
Shivering
Chills
Anorexia
Malaise
What are Labile tissues?
Examples
- Continuously dividing
- HSC in bone marrow, surface epithelium of skin, oral cavity, vagina, cervix, gi, uterus urinary tract
What are the 3 types of permanent tissue?
1) Cardiac
2) Neuronal
3) Skeletal muscle
Where do progenitor cells of the liver reside?
Canals of Hering
What mediator is responsible for the priming phase of liver regeneration?
Growth factor phase?
Termination phase?
IL-6
HGF and TGF-α
TGF-B
The sprouting of new blood vessels due in the inflammation/angiogenesis stage of scar formation is due to what?
What stimulates the proliferation of endothelial cells and the migration of macrophages and fibroblasts to the damaged area?
- VEGF-A
- FGF-2
What GFs play a role in structural maturation of new vessels and angiogenesis?
Ang1 and Ang2
What is the receptor for Ang1?
Tie2 (tyrosine kinase receptor)
What GF regulates sprouting and branching of new vessels via cross talk with VEGF; ensuring new vessels formed have proper spacing to effectively supply the healing tissue?
Notch
What GF participates in the process of vessel sprouting via interactions with integrin receptors by providing scaffold for vessel growth?
ECM proteins
What enzymes in the ECM degrade the ECM to permit remodeling and extension of the vascular tube?
Matrix metalloproteases (MMPs)
What regulates the deposition of CT in scar formation?
Activated by what?
- PDGF, FGF-2, TGF-B
- M2 macrophages
In the remodeling of CT, what degrades collagens? What are they dependent upon?
What inhibits them to shut down activity?
What is activated and inhibited during scar formation
- MMPs, metal ions (zinc)
- TIMPs
- MMPs are activated to remodel the deposited ECM and then shut down by TIMPs
What cells contribute to contraction of the scar over time?
Myofibroblasts
What is anchored to the PM and cleaves and releases extracellular domains of cell-associated cytokines and GFs like TNF, TGF-B?
ADAMs
If the injury involves only the epithelial layer, how does wound healing progress?
Example?
- Primary union or healing by first intention
- Sutures
When cell loss is extensive, as in large wounds, abscesses, ulceration, and ischemic necrosis, how does healing occur?
Secondary intention (AKA healing by second union)
An accumulation of excessive amounts of collagen creating a raised scar is called what?
Generally develop after what type of injury to where?
- Hypertrophic scar
- Thermal or traumatic injury that involves the deep layers of the dermis
Scar that grows beyond the boundaries of the original wound but does not regress is called what?
Common in what population?
Characterized by what?
Common in what part of the body?
- Keloid
- African Amerixans
- Type III collagen
- Earlobe, face, and UE’s
Where are contractures prone to develop?
Commonly seen when?
- Palms, soles, anterior throax
- After burns and compromise the movement of joint
What do steroid inhibit?
- Phospholipases
- Therefore the entire PG/LT pathway
What is the histological appearance of granulation tissue?
- Pink, soft, and granular gross appearance
- Characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries (angiogenesis) in a loss extracellular matrix, often w/ admixed macrophages and other inflammatory cells
Which GF recruits smooth muscle cells to site of angiogenesis?
Which GF suppresses endothelial proliferation and migration and enhances the production of ECM proteins?
- PDGF
- TGF-β
What is the most important cytokine for the synthesis and deposition of connective tissue proteins?
How are the levels of the cytokine primarily regulated?
- TGF-β
- Posttranscriptional activation of latent TGF-β, the rate of secretion of the active molecule, and factors in the ECM (notably integrins)
Which cytokine stimulates fibroblast migration and proliferation, increases synthesis of collagen and fibronectin, and decreases degradation of ECM due to inhibition of MMPs?
TGF-β
Which MMPs degrade fibrillar collagen?
Interstitial collagenases (MMP-1, 2, 3)
Which MMPs degrade amorphous collagen and fibronectin?
Gelatinases (MMP-2,9)
Which MMPs degrade proteoglycans, laminin, fibronectin, and amorphous collagen?
Stromelysins (MMP-3, 10, 11)
Glucocorticoid administration results in weakness of the scar due to inhibition of TGF-β production and diminished fibrosis; what is one scenario where they prescribed for these effects?
Corneal infections to reduce the likelihood of opacity that may result from collagen deposition
By day 5 of healing in a first intention (primary union) neurovascularization reaches peak as granulation material fills the incision space. Fibroblasts are brough to the site by which chemokines/GFs?
Which GFs and chemokines trigger their proliferation?
- TNF, PDGF, TGF-β, and FGF (brings them in)
- PDGF, EGF, TGF-β, FGF, IL-1 and TNF (cause them to proliferate)
- Macrophages are the main source of these factors
In most organs, such as the lung and kidney what is the main source of collagen?
How about in liver cirrhosis?
- Myofibroblasts (most organs)
- Stellate cells (liver cirrhosis)
Formation of excessive amounts of granulation tissue that protrudes above the level of the surrounding skin and blocks reepithelialization is known as?
Exuberant granulation (AKA proud flesh)
Fortunately rare, incisional scars or traumatic injuries may be followed by exuberant proliferation of fibroblasts and other CT elements that may recur after excision are called?
Desmoids or aggressive fibromatoses, these neoplasms lie in the interface between benign and malignant (though low-grade) tumors
