Pathology- Inflammation, wound healing Flashcards
Arachidonic acid
: mediator of acute inflammation; released from phospholipid membrane by phospholipid A2
- acted on by either cyclooxygenase = prostaglandins, or
- 5-lipooxygenase = leukotrienes
Significance of NF-KB
NF-KB is a nuclear transcription factor that is activated upon TLR activation by PAMPs
-TLRs are present on APCs and lymphocytes
Which prostaglandins mediate vasodilation and increased vascular permeability?
-vasodilation = arteriole; increased vascular permeability = post-capillary venule
: “DIE” PGD2 PGI2 PGE2
What are the functions of PGE2?
:vasodilation, vascular permeability, FEVER & PAIN
What are the important leukotrienes? What are the effects?
LTC4, LTD4, LTE4- THINK SM CONTRACTION
: vasconstriction, bronchospasm, increased vascular permeability
What are the main mediators of attracting PMNs?
- LTB4
- IL-8
- C5a
- bacterial products
How are mast cells activated?
- Cross-linking IgE
- complement (C3a, C4a, C5a)
- tissue trauma
Function of histamine
Vasodilation and increased vascular permeability
Note: delayed response is production of leukotrienes (recall hypersensitivity I) –> this is how the response is maintained
Hageman factor (Factor XII)
:inactive pro-inflammatory protein produced in liver; activated when exposed to subendothelial collagen
- activates coagulation cascade
- activates complement
- activates kinin system: kinin cleaves kininogen to bradykinin = vasodilation and increased vascular permeability + pain
Rubor & Calor
: d/t vasodilation occurs via SM relaxation of arteriole
- Key mediators: histamine, prostaglandins, leukotrienes
Tumor
:swelling; d/t leakage of fluid from postcapillary venules into interstitial space (exudate)
-Key mediator: histamine which causes endothelial cell contraction & tissue damage resulting in endothelial cell disruption
Dolor
:pain
-Key mediators: bradykinin and PGE2 –> sensitize sensory nerve endings
Fever
pyrogens (LPS from bacteria) cause macrophages to release IL-1, IL-6 and TNF
-IL-1 and TNF increase cyclooxygenase activity (PGE2) in perivascular cells of the hypothalamus which raises the temperature set point
Margination
- vasodilation at the arteriole slows blood flow at the POST-CAPILLARY VENULE
- cells marginate to the periphery of the vessel
P-selectin
:important in rolling, expressed on endothelial cells; released from weibel palade body of endothelial cells, mediated by histamine
-binds sailyl-Lewis X on leukocytes
E-selectin
:important in rolling, expressed on endothelial cells; induced by TNF and IL-1
-binds sailyl-Lewis X on leukocytes
What are the cellular adhesion molecules? What induces their expression?
- ICAM-1 (CD54) & VCAM (CD106)
- expressed on the endothelium, induced by TNF and IL-1
What are integrins? Function?
:bind to cellular adhesion molecules on the endothelial cell surface to promote tight adhesion
- CD11/18 integrins, (LFA-1, Mac-1), VLA-4 integrin
- Integrins are upregulated on leukocytes by C5a and LTB4
What are the steps of leukocyte extravasation?
- Margination and rolling
- Tight binding
- Diapedesis (transmigration)
- Migration and chemotaxis
What is the respiratory burst?
:generation of HOCl within the phagolysosome of the phagocytes
-O2 coverted to superoxide by NADPH oxidase
-Super oxide converted to hydrogen peroxide (H2O2) by superoxide dismutase
H2O2 converted to HOCL (bleach) my myeloperoxidase
Myeloperoxidase deficiency
:defective conversion of H2O2 to HOCl
- patients usually asymptomatic; presentation may be recurrent candida infections
- NORMAL nitroblue tetrazolium test b/c respiratory burst intact
Acute inflammation
:the hallmark of acute inflammation is NEUTROPHILS
- usually peaks around 24 hrs but can be longer;
- THE MAIN POINT IS IF PMNs ARE AROUND =ACUTE INFLAMMATION
Macrophage roles:
:peak around 2-3 days after inflammation begins; they are the “manager”
- Resolution and healing: anti-inflammatory cytokines IL-10 and TGF-B
- Continue acute inflammation: IL-8 to call in PMNs
- Abscess formation: acute inflammation surrounded by fibrosis
- Chronic inflammation: macrophages present antigen to CD4 helper cells which secrete cytokines to promote chronic inflammation
What cell(s) characterize a granuloma?
Epitheliod histiocytes (macrophages with an abundant pink cytoplasm) -Giant cells and a rim of lymphocytes
What interactions prompt granuloma formation?
- Macrophages present via MHCII to CD4 helper cells
- Macrophages secrete IL-12 which causes Th1 subtype differentiation
- Th1 cells secrete IFN-gamma –> converts macrophages to Epitheliod histiocytes
- TNF-a from macrophages maintains granuloma
Recall: anti-TNF-a drugs cause breakdown of granuloma so always test for latent TB before starting drug
What are liable tissues?
:posses stem cells that continuously cycle to regenerate the tissue.
Ex: small and large bowel, skin, bone marrow
Where are the stem cells in the small and large bowel?
mucosal crypts
Where are the stem cells of the skin?
Basal layer of the dermis
What is the hematopoietic stem cell surface marker?
CD34
What are stable tissues?
: comprised of cells that are quiesent (G0) but can reenter the cell cycle to regenerate tissue when necessay
Ex. liver or renal cells
What are permanent tissues?
:lack significant regenerative capacity
-Heart, skeletal muscle, nerves
What is the composition of granulation tissue?
Fibroblasts - lay type III collagen
capillaries
myofibroblasts
What is the difference between granulation tissue and a scar?
type III collagen is replaces with type I collagen
-collagenase removes type III collagen; requires zinc a a cofactor
TGF-a
epithelial and fibroblast growth factor
TGF-B
fibroblast growth factor and inhibits inflammation
PDGF
:platelet derived growth factor; growth factor for endothelium, smooth muscle, and fibroblasts
-secreted by platelets and macrophages
VEGF
:vascular endothelial growth factor; important in angiogenesis
FGF
:fibroblast growth factor; important in angiogenesis also mediates skeletal muscle development
What are the mediators of wound healing?
PDGF, FGF, EGF,TGF-B,TGF-a,VEGF
EGF
Epidermal growth factor stimulates cell growth via tyrosine kinases
Primary intention
:form of cutaneous wound healing; wound edges are approximated (eg. suture) –> leads to minimal scar formation
Secondary intention
:form of cutaneous wound healing; edges are not approximated. Granulation tissue fills the defect & myofibroblasts contract the wound forming a scar
Give reasons as to why wound healing would be delayed.
- Infection –> continued inflammation impairs healing
- Vitamin C deficiency: important cofactor in the hydroxylation o proline/lysine procollagen residues
- Copper deficiency: cofactor for lysyl oxidase which cross-links lysine and hydroxylysine to form stable collagen
- Zinc deficiency: cofactor for collagenase; which replaces type III collagen with type I collagen
Hypertrophic Scar
:excess production of scar tissue (type I collagen) that is localized to the wound
- collagen arrangement is parallel
- infrequently recur following resection
Keloid
:excess production of scar tissue (type III collagen) that extends beyond the borders of the wound
- collagen is disorganized
- frequently recur following resection
- more common in AA; classically effects earlobes, face and upper extremities
Shock
Refer to FA pg 222 and shock chart
Chromatolysis characteristics:
: process involving the neuronal cell body following axonal injury or ischemia
-Changes reflect increase in protein synthesis in an effort to repair the damaged axon:
1. round cellular swelling
2. displacement to the nucleus to the periphery
3. dispersion of nissl substance throughout the cytoplasm
Note: nissl substance = RER
Dystrophic calcification
Calcium deposition in tissues secondary to necrosis; tends to be localized
- necrotic tissue acts as a nidus for calcification
- in the setting of normocalcemia
Metastatic calcification
widespread calcification in normal tissue secondary to hypercalcemia or high phosphate
- predominately in interstitial tissues of kidney, lungs and gastric mucosa
Transudate
:transudate is Thin; due to increase in hydrostatic pressure, decrease in oncotic pressure, or Na retention
- hypocellular
- protein poor
- specific gravity <1.012
Exudate
: due to inflammation/infection or malignancy
- cellular
- protein rich
- specific gravity >1.012
ESR
:erythrocyte sedimentation rate; products of inflammation coat RBCs and cause aggregation; when aggregated RBCs fall at a faster rate within the test tube
- Increased ESR: anemia, infection/inflammation, cancer, pregnancy,
- Decreased ESR: polycythemia, sickle cell, CHF
Patient- 5 y/o child presents with sudden lethargy, nausea, vomiting, bloody stool. You suspect the child got into a bottle of prenatal vitamins. Diagnosis?
Iron poisoning; iron is extremely corrosive to the GI mucosa; metabolic acidosis is secondary to mitochondrial poisoning
- most sever in kids< 6 yrs
- acute:nausea, vomiting, gastric bleeding, lethargy
- chronic:metabolic acidosis, scarring leading to GI obstruction
Autopsy of 75y/o woman shows colon mucosa shows yellow/brown granular pigment in macrophages. What is it?
Lipofuscin: wear and tear pigment associated with normal aging
- formed by oxidation and polymerization of auto-phagocytosed organelles
- deposits in heart, liver, kidney, eye and many organs
