The function of LPS in gram-negative infections
PAF and NO= Peripheral vasodilatation
PGE2 functions (4)
Increased vascular permeability
Vasodilation
Fever
Pain
Leukotriene (C,D,E) functions (3)
Bronchoconstriction-Think Asthma after aspirin use Vasoconstriction Increased Permeability (via pericyte contraction)
classical complement pathway is activated by
IgG or IgM binding C1, so C2 and C4 will be low.
Alternative pathway activated by
Microbes directly activate complement, so C2 and C4 will remain normal.
Common product of all 3 complement pathway
C3 convertase, which produces C3a and C3b
C3a and C5a functions
Anaphylatoxins –> trigger mast celld egranulation
C3b function
Opsonin
3 key mediators of Redness and Warmth
Bradykinin
HIstamine
PGs
2 key mediators of swelling
Histamine
Tissue damage
2 mediators of pain
Bradykinin
PGE2
Mechanism of fever in bacterial infection/sepsis
Pyrogens from bacteria cause macrophages to release IL1 and TNF
IL1 and TNF increase COX in perivascular cells of hyopthal –> increase set point
What do selectins bind to on the leukocyte?
Silalyl Lewis X
3 structures mediating cellular adhesion
ICAM/VCAM on endothelial cell
Integrins on leukocyte
Leukocyte adhesion deficiency is a defect in
Integrins
3 hallmark features of LAD
1- Delayed separation of umbilical cord
2- Increased neutrophil count (detachment of marginated pool)
3- recurrent bacterial infection w/o pus formation
Chediak Higashi defect
Defective lysosomal trafficking regulator Gene (LYST)
Results in microtubule defects and poor phagolysosome formation
Clinical features of Chediak higashi (5)
- Recurrent pyogenic infections
- albinism (unable to move melanin to keratinocytes
- peripheral neuropathy
- Pancytopenia (no microtubules = no cell division)
- Giant granules in granulocytes
NADPH Oxidase deficiency
Chronic granulomatous disease (unable to produce reactive oxygen species)- get granuloma in bacterial infection!
CGD inheritance
X linked recessive
Hallmark of CGD
Recurrent infection with catalase-positive organisms
Pseudomonas, Candida, Ecoli, Staph
How to differentiate b/w CGD and MPO deficiency
Check free radical is present or not
2 mechanisms by which neutrophils kill
O2 dependent»_space;> O2 independent (lysosyme)
Major macrophage killing mechanism
Lysozyme…O2 independent (Stroke)
2 cytokines produced by TH1
IL2
INFy
TH2 CD4 cells secrete
IL4
IL5
Hallmark histology of granulomatous inflammation
Epithelioid Histiocytes (macrophages with lots of pink cytoplasm) Giant cells + a Rim of lymphocytes+ a rim of fibrosis
2 cytokines involved in granuloma formation
INFy from TH1 cells –> macrophages become epithelioid histiocytes
XLinked Agammaglobulinemia defect
Phagocytosis defect
C1 inhibitor normal function
Prevents activation of compliment cascade
3 classic symptoms in Sjogren
Keratoconjunctivitis
Xerostomia (dry mouth)
Bilateral parotid enlargement
Autoantibodies found in Sjogren
antiribonucloprotein: SSA (anti Ro) and SSB (antiLa)
ANA
Limited Scleroderma findings
CREST Syndrome
Calcinosis Raynaud Esophageal Dysmotility Sclerodactyly Telangiectasias
Skin involvement of face and hands only
Limited scleroderma autoantibody
Anti-centromere
Diffuse scleroderma findings
Widepsread skin involvement with rapid progression
What is anti Scl 70
Anti DNA topo I
General principle to determine which tissues repair and which regenerate
Tissues that are labile will regenerate (occasionally stable)
Permanent tissue will repair
3 Granulation tissue components (red and granular in gross)
Fibroblasts
Proliferating blood vessels
Myofibroblasts
Type 1 collagen is found in which 4 structures
Bone
Skin (delayed wound healing)
Tendon
Fascia
Type 2 collagen is found in 3 structures
Cartilage (hyaline included)- in Osteoarthritis
Vitreous body
Nucleus pulposus
Type III collagen found in 4 structures
Reticulin (skin, blood vessels, uterus, granulation tissue)
Type III collagen deficiency is found in which disease
Ehler Danlos (visceral rupture)
Type IV collagen found in 3 structures
Basement Membrane
Basal Lamina
Lens
Function of fibroblasts in wound healing
Lay down type III collagen
Collagen difference between granulation tissue and scar
Granulation = 3 Scar = 1
Cell type that contracts the wound
Myofibroblasts
Importance of Vitamin C in wound healing
Cofactor for hydroxylation of proline and lysine
Vitamin C deficiency results in
Failure of collagen cross linking
Keloid collagen type
Type I
Steps of healing
Hemostasis Phase. Hemostasis is the process of the wound being closed by clotting. …
Inflammatory Phase. …
Proliferative Phase. …
Maturation Phase
Organ findings in septic shock (or any shock)
Lung- ARDS- what it is the composition of the hyaline membrane?
Brain- Laminar cortical necrosis
Kidnet- tombstone appearance
Integrin function
Integrins interact with the extracellular matrix proteins (e.g., fibronectin) and the epithelium
Fibronectin function
Adhesive glycoproteins such as fibronectin help to maintain a cellular scaffolding for growth and repair, but they do not contract, early to develop.
DM why delayed healing (similat with abundant farry food intake)
glycosylation of ECM, reduced cross linking
Starvation (shipwreck) and Vit C deficiency- why delayed healing
deficiency of collagen and Failure of collagen cross-linking
The most important cell in healing
macrophage
Example of resolution
Lobar pneumonia
Compensatory hyperplasia see in…
Liver
Phases of healing
hemostasis (1 - 24h)
inflammation (1 - 5d)
proliferation (4 - 21d)
granulation tissue (newly laid collagen with neovascularization) forms
epithelialization occurs from surrounding basal keratinocytes and hair follicle basal cells
maturation (21d to up to 7/8 weeks depending on the tissue)
type III collagen remodeled to type I collagen
vessels mature and excess vasculature involutes
erythema and raised appearance of wound resolves
Why complete regeneration occur in Hepatitis A infection
Because 1) stromal tissues (ECM) are not damaged and 2) because of hepatocyte beling Stable cell in HAV infection! only cells die…they regenerate without fibrosis!
The type and extent of tissue injury affects the subsequent repair. Complete restoration can occur only in tissues composed of stable and labile cells; even then, extensive injury will probably result in incomplete tissue regeneration and at least partial loss of function. Injury to tissues composed of permanent cells must inevitably result in scarring with, at most, attempts at functional compensation by the remaining viable elements. Such is the case with healing of a myocardial infarct.
Wound Strength after repair
approximately 70-80% of the strength of normal skin
Wound strength with stuture is removed (1 week)?
When sutures are removed, usually at 1 week, wound strength is approximately 10% of that of unwounded skin, but this increases rapidly over the next 4 weeks.
Growth factors for angiogenesis
VGEF (the Notch signaling pathway ), PDGF, Basic FGF
……………….. stimulates fibroblast migration and proliferation, increased synthesis of collagen and fibronectin
TGF-β
The degradation of collagens and other ECM components is accomplished by a family of………………….
matrix metalloproteinases (MMPs)>A family of enzymes related to MMPs is called ADAM (a disintegrin and metalloproteinase seen in TTP).
The skin blister resulting from a burn represents the accumulation of ………………………
serous fluid (due to direct endothelial injury)
Morphology: fibrinous exudate ?
Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum
Purulent inflammation is characterized by……………….
the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid
Abscesses are …………………………
localized collections of purulent inflammatory tissue caused by suppuration buried in a tissue, an organ, or a confined space (liquefactive necrosis) surrounded by granulation tissue.
Suppurative inflammation
A type of purulent inflammation. Pus leaks out. Usually by an infection with bacteria that cause liquefactive tissue necrosis, such as staphylococci; these pathogens are referred to as pyogenic (pus-producing) bacteria. A common example of an acute suppurative inflammation is acute appendicitis
Empyema
The collection of pus in a cavity in the body, especially in the pleural cavity.
Marphan defect?
Fibrillin gene, elastic tissue
