when does the following arrive at the wound site 

leukocytes

when does the following arrive at the wound site

Polymorphonuclear leukocytes

time of arrival

macrophages

When do the following arrive at the wound site

Fibroblasts, myofibroblasts, pericytes, and smooth muscle cells

most abundant collagen .

ubiquitous.

skin, bone, etc

if there are mutation in the gene that encodes this molecule, result in assembly defects the triple helix, resulting in increased bone fractures, thin dermis, and easy bruising. 

binds IgE molecule

contains electron dense granules 

play a role in allergic reactions 

granules include heperin

associated with allergic reactions

parasite associated reactions

chronic inflammation

modulates mast cell mediated reactions

They express IgA receptor

contains large granules

follows inflammation in which there is a proliferation and migration of connective tissue cells and an ingrowth of newcells called angiogenesis. 

it involves activation of collagen, tissue remodeling, the colagen then becomes stronger by a process called wound contration. tihs is where the scar gets more dense : fibrosis 

Liver cells always contain some fat, because free fatty acids released from adipose tissue are taken up by the liver. there they are oxidized, or converted to triglycerides. most of the newly synthesized triglycerides are secreted by the liver as lipoproteins. 

fat storage is reversible 

25% of the body's total ____ content is stored in a storage pool composed of the iron storage proteins ferritin and hemosiderin. 

ferritin: in the liver and bone marrow (but present in all cells)

Hemosiderin: found mainly in spleen, boone marrow, and kupffer cells of the liver. 

a condition in which the body's total iron content was increased leading to a progressive accumulation of hemosiderin. 

in this condition, iron is present not only in the organs where it is normally found but throughout the body. 

Iron deposition is so severe that it damages vital organs such as the heart , liver, and pancreas. 

can result from a genetic abnormality in iron absorption (hereditary hemochromatosis)

it may occur after multiple blood transfusions 

excessive iron storage: increase in cancer risk 

storage of exogenous pigments

it specifically refers to the storage of carbon particles in the lung and lymph nodes. 

more prevelent in urban areas 

the particles accumulate in macrophages and are transported to ymph nodes where the indigestible material is stored forever within the macrophages. 

formed and largely stored in the liver and to a lesser extent in the muscles. 

it is depolymerized to glucose and liberated as needed. 

the storage of _____ is normally regulated by the blood glucose concentration. 

pathological cell death.

elicits inflammatory response 

different types : coagulative, liquefactive, fat, caseous, fibrinoid

light microscopic alterations in dead or dying celll. 

the outline of the cell is maintained shortly 

cytoplasm is deeply eisophinic

clumped chromatin in the nucleus that gets redistributed along nuclear membrane.

three morphologic changes: Pyknosis, karyorrhexis, and karyolysis

liquefactive necrosis 

when the rate of dissolution of the necrotic cell is considerably faster than the rate of repair. 

often results in an absess 

shows presence of triglycerides in adipose tissue. 

as a result from pancreitis /trauma, adipose tissue is altered. digestive enzymes are released from the injured pancreas. these enzymes digest the pancreas itself along with adipose. 

resembles tuberculosis

dead cells persist indefinately

fail to maintain cell outline 

deposition of mineral salts of calcium is a normal process in the ormation of bone from cartilage. 

calcium entry into dead or dying cells is usual, owing to the inability of such cells to maintain a steep calcium gradient. 

macroscopic deposition of calcium salts in injured tissues. 

requires the persistance of necrotic tissue 

if calcification occurs in aortic or mitral valves, it will lead to impeded blood flow because it produces inflexible valve leaflets and narrowed valve orafices

mammograph: detects calcification in breast cancer

deranged calcium metabolism in contrast to dystrophic calcification which has an origin in cell injury.

associated with hypercalcemia. 

formation of stones containing calcium may occur in sites such as the gall blader, renal pelvis, bladder, and pancreatic duct. 

Inflammatory response to injury

1. tissue injury

2. chemical mediators and cells are released from plasma following tissue injury.

3. vasodilation and vascular injury lead to leakage of fluid into tissues (edema)

4. platelets are activated to initiate clot formation and hemostasis, and to increase vascular permeability via histamine release. 

4. vascular endothelial cells contribute to clot formation, retract to allow vascular permeabilty, and anchor circulating neutrophils via their adhesion molecules. 

5. microbes intiiate activation of complement ccascade which recruit neutrophils to site of tissue injury. 

6. neutrophils eliminate microbes and remove damaged tissue so that repair can begin.

Initiation of Inflammatory response 

Accute inflammation process

results in activation of soluble mediators and recruitment of inflammatory cells to the area. 

molecules are released from the damaged cells and from the extracellular matrix

• these molecules alter the permeability of adjacent blood vessels plasma, soluble molecules, and circulating inflammatory cells. 

Inflammatory Response 

Destruction 

______ of the damaging agent brings process under control 

• Enzymatic digestion and phagocytosis reduce or eliminate foreign material/infectious organisms. 
• damaged tissue components are also removed. 

Inflammatory Response 

Termination 

mediated by intrinsic anti-inflammatory mechanisms that limit tissue damage and allow for repair and a return to normal function. 

intrinsic methods are in place to terminate inflammatory response

1. increased vascular permeability

2. intravascular stimulatoin of platelets and inflammatory cells, and release of soluble mediators 

3. recruitment of neutrophils to the injured site. 

a result of initiation of Inflammatory response 

it leads to accumulation of fluid and plasma components in tissues affected by inflammation.

• normally, fluid exchange occurs between intravascular and extravascular spaces, with the endothelium forming a permeability barrier. 
• disruption of this barrier is hallmark of acute inflammation
• endothelial cell contraction causes vascular leakage : EDEMA 

normally the ______ form a permeability barrier. they are connected to each other by tight junctions and separated from the tissue by a limiting basement membrain. 

disruption of its barrier function is hallmark of acute inflammation. 

damage to this barrier causes edema, becaues it allows leakage of fluid and cells into the extravascular space. 

• platelets
• kinins
• complement
• coagulation cascade

activated by inflammatory mediators produced at the site of injury. 

they further increase vascular permeability and edema. 

separation of the endothelial cells from the underlying basement membrane. 

this is a result of severe direct injury to endothelium 

prolonged escape of fluid elements from the microvasculature occurs as a result. 

Vascular events after initiation 

3. Recruitment of neutrophils to the injured site. 

chemotactic factors recruit leukocytes (neutrophils) from the vascular compartment into the injured tissue. 

once present in the tissues, the neutrophils eliminate offending agents so that damaged components can be removed and tissue repair can commence. 

these cells can also secrete additional mediators 

explains regulation of fluid transport accross vascular walls 

"Interchange of fluid between vascular and extravascular compartments results from a balance of forces that draw fluid into the vascular space or out into tissues."

• hydrostatic pressure
• oncotic pressure 
• osmotic pressure
• lymph flow 

obstruction of veneous outlfow 

its a condition associated with edema 

it is a characteristic of Platelets: promotes clot formation

a fluid accumulation  because of obstruction of lymphatic flow

could be a result of surgical removal of lymph nodes or tumor obstruction 

Inflammatory edema 

Triple response 

1. dull red line developed at the site of mild trauma to skin 

• transient vasoconstriction of arterioles 
• process resolves within seconds to minutes

2. this was followed by a "flare"  (red halo) 

• vasodilation of precapillary arterioles 
• increases blood flow to the tissue (hyperemia)
• caused by a release of mediators 
• responsible for redness and warmth at injured site

3. Next came a wheal (swelling)

• Increase in endothelial cell barrier permeability 
• results in edema 
• the extra fluid can be cleared thru the lymphatics within minutes to hours. 

originate from both plasma and cellular sources 

they are generated at sites of injury

they bind to specific receptors on endothelial cells, causing cell contraction and gap formation (reversible )

• the gaps lead to extravasation (leakage) of intravascular fluids into the extravascular space. 

1. coagulation cascade

2. kinin generation

3. compliment system 

hagemen factor

clotting factor XII

• generated within plasma 
• activated by exposure to (-) charged surfaces like basement membranes etc.. 
• it triggers activation of additional plasma proteases leading to :

amplify the inflammatory response 

they are potent inflammatory agents formed in the lasma and tissue. 

they regulate multiple physiological processes: blood pressure, contraction/relaxation of smooth muscle, cell migration, inflammatory cell activation, and inflammatory mediated pain responses. 

short lived bc they are degraded by kinases 

they amplify the inflammatory response by stimulating local tissue cells and inflammatory cells to generate additional mediators 

1. alternative

2. classical

3. mannose binding 

complement type : 

Anaphylatoxins

Complement type: 

opsonins 

a specific molecule (ex IgG) binds to surface of bacterium. 

the process enhances phagocytosis by enabling receptors on phagocytic cell membranes to recognize and bind the opsonized bacterium. 

complement type: 

Pro inflammatory molecules 

Cell derived mediators of Inflammation 

vasoactive mediators 

circulating platelets

basophils

PMNs

Endothelial cells 

macrophages/monocytes

mast cells, and the injured tissue itself 

Platelet Activating Factor

PAF

potent inflammatory mediator derived from membrane phospholipids. 

synthesized by all activated inflammatory/endothelial/injured cells 

function: 

Stimulates platelets, neutrophils, monocyte/macrophages, endothelial cells, and vascular smooth muscle cells. 

potent vasodilator

cell derived inflammatory hormones . 

produced at sites of inflammation

regulate inflammatory response. 

autocrine, paracrine, endocrine effect. 

through production of cytokines, macrophages are pivotal in orchestrating tissue inflammatory responses. 

cytokines activate endothelial cells to express adhesion molecules and to release cytokines, chemokines, and ROS. 

signal transducing, bactericidal, and cytotoxic molecules 

chemically reactive molecules derived from oxygen 

normally rapidly inactivated, can be toxic to cells. 

they activate signal transduction pathways and combine with proteins lipids, and dna. (oxidative stress) leads to loss of function or cell death

the major cells of inflammatory response

include : Neutrophils, T and B lymphocytes, monocytes , macrophages, eisonophils, mast cells, and basophils. 

stored in bone marrow, circulate in the blood. 

activated in response to phagocytic stimuli, cytokines, chemotactic mediators,and antigen antibody complexes that bind receptors on their cell membrane

neutrophils receptors recognize FC portion of IgG and IgM

regulate vascular permeability and bronchial smooth muscle tone, especially in allergic hypersensitivity reactions. 

binds IgE molecules 

circulate in  blood. recruited to tissue, similar to PMN. 

IgE mediated reactions

hypersensitivity, allergic, and asthmatic responses. 

possess IgA receptors and contain large granules 

defense against parasites. 

process where leukocytes interact with endothelial cell selectins 

after _____ comes rolling and then transmigration thru the vessel wall and under the influence of chemotactic factors, the leukocytes will migrate thru extra vascular tissue to the site of injury 

cytokines limit it by producing TNF a. it inhibits release of further inflamatory mediators. 

protease inhibitors, lipoxins, glucocorticoids, and kinases, and phosphatases all regulate inflammation 

arrival at wound: 

stem cells 

chemical signals 

the response of cells to these chemical signals is the most important mechanism of wound healing 

excess collagen deposition

this is the basis of connective tissue diseases such as keloids and scleroderma and can accompany chronic damage to organs. 

all _______ chains have helical segments of glycine, proline, and hydroxyproline, and hydroxylysine. 

every third amino acid is glycine, important for triple helix structure 

complex

each molecule is made by self association of three a chains that wind around each other to form a triple helix. 

triple helix includes members from an a chain family that is unique for each collagen type

successful synthesis of _______:

1. allignment of three chains 
2. formation of triple helix
3. cleavage of noncollagenous terminal peptides
4. molecular alignment and association
5. covalent cross linking

types 1, 2, 3, V, and XI

1 2 and 3 are most abundant 

they have slow turnover and resistant to proteinase digestion except for in MMPs

contain globular domains that prevent fibril formation

contain a varied number of nonhelical domains  that interrupt triple helix 

act as transmembrane proteins

means both white and hard

this is a name for collagen 

• clotting factors 
• extracellular matrix proteins
• latent growth factors and growth factor binding proteins
• receptors for matrix molecules and cell to cell adhesion molecules
• other MMPs (matrix metalloproteinases  enable cell to migrate thru stroma by degrading matrix proteins) 
• other proteinases
• proteinase inhibitors
• chemotactic molecules 

1. thrombosis: formation of a growth factor rich barrier having significant tensile strength
2. inflammation: necrotic debris and microorganisms must be removed by neutrophils; the appearance of macrophages signals and initiates repair 
3. reepithelialization: newly formed epithelium establishes permanent barrier to microorganisms and fluid 

first stage in skin repair

it is a clot referred to as a scab or eschar after drying out

it forms a barrier on the wounded skin to invading surface microorganisms. 

the barrier prevents the loss of plasma and tissue fluid 

formed from plasma fibrin, rich in fibronectin 

it contains contracting platelets, an initial source of growth factors 

when the thrombus has been penetrated by regenerating epithelium, the scab detatches 

second step of early skin repair 

neutrophils remove necrotic debris, and the appearance of macrophages signals and initiates repair, such as growthfactors that stimulate fibroblast (early responders to injury, collagen secreting cells)  proliferation, collagen secretion, and neovascularization. 

it is followed by reepithelialization 

macrophages release growth factors that stimulate _______ proliferation

_______ are early responders to injury

they are cells that secrete collagen 

involved in the inflammatory, proliferative, and remodeling phases of wound repair. 

1. granulation tissue formation and function: this specialized organ of repair is the site of extracellular matrix and collagen secretion. vascular, edematous, insensitive, resistant to infection
2. contraction: fibroblasts along with other cells transform into myofibroblasts which contain actin. they link together along with collagen, and contract stimulated by TGF 

transient, specializd organ of repair. replaces the provisional matrix. like the placenta, it is only present where and when it is needed. 

a mixture of RBC and fibroblasts first appear, then the provisional matrix is developed along with patent single cell lined capillaries, surrounded by fibroblasts and inflammatory cells. 

to develop __________, key step is recruitment of monocytes to the site of injury by chemokines. 

activated macrophages coordinate the development of granulation tissue through the release of growth factors and cytokines 

2 major components of _______ : cells (mainly fibroblasts)  and proliferating cappilaries 

1. begin with hemorrhage into the tisues
2. a fibrin clot forms and fills the gap created by the wound
3. fibronectin is crosslinked to fibrin, collagen, and other extracellular matrix components. this provides stabilization of the wound for 0-4 hrs. 
4. macrophages are recruited to the wound area
5. binding of fibronectin to cell membranes and collagens, proteoglycans, dna, and bacteria (opsonization) facilitates phagocytosis by these macrophages.  this contributes to the removal of debris for 1-3 days. 
6. fibronectin, debris, and bacterial products are now chemoattractants for a variety of cells that are recruited to the wound site. 2 -4 days. 
7. as a new extracellular matrix is deposited at the wound site, the initial fibrin clot is lysed by a combination of extracellular proteolytic enzymes and phagocytosis 2-5 days 
8. along with fibrin removal is a deposition of temporary matrix formed by proteoglycans, glycoproteins, and type 3 collagen 2-5 days. 
9. final phase of repair. 
10. temporary matri is removed by extra/intracellular digestion. the matrix rich in type 1 collagen is deposited. 5 days - weeks. 

extracellular signals in wound repair

1. coagulation 

source: plasma, platelets 

effects: thrombosis & chemoattraction of subsequently involved cells. 

wound repair 

2. inflammation 

source: neutrophil, macrophages, keratinocytes

effects: attract monocytes and fibroblasts; differentiates fibroblasts and stem cells 

1. coagulation 

• start with plasma and platelets
• they form thrombosis 
• chemoattraction of subsequently involved cells (neutrophils and macrophages)