inflammation and repair Flashcards
inflammation
a complex reaction important in the process of repair that leads to the accumulation of fluid and leukocytes (white blood cells) in vascularized tissue. it is fundamentally a protective response that, if dysregulated, can cause harm
acute
short duration, most characterized by vascularized tissue. it is fundamentally a protective response that, if dysregulated, can cause harm
acute
short duration, mostly characterized by vascular changes that lead to edema of surrounding tissues and infiltration by neutrophils (also called polymorphonuclear leukocytes (PMNLs) or polys
chronic
longer duration, characterized by lymphocytes and macrophages (monocytes), tissue destruction by these cells and an attempt at at tissue repair via proliferation of blood vessels (angiogenesis) and connective tissue (fibrosis and scarring)
classic local signs of inflammation
rubor (redness)
swelling (tumor)
pain (dolor)
warmth (calor)
systemic signs of inflammation
fever
increased white cell count
enlargement of lymph nodes
associated microscopic events of redness & heat
dilation of microcirculation
associated microscopic events of swelling
permeability of vessels leads to exudate formation in tissues
associated microscopic events of pain
pressure on nerves by exudate, release of chemical mediators inducing pain
associated microscopic events of loss of normal tissue function
the result of swelling and pain
inflammatory response
1) injury
2) constriction of the microcirculation
3) dilation of small blood vessels
4) increase in permeability of small blood vessels
5) exudate leaves small blood vessels
hyperemia
increased blood flow that floods the capillary beds in the injured tissue
responsible for redness (erythema) and heat
exudate
inflammatory fluid formed as a reaction to injury of tissues and blood vessels
serous exudate
composed mainly of plasma fluids and proteins with a few white blood cells
purulent exudate (supparation)
contains tissue debris and many white blood cells, in additon to plasma fluids and proteins
fistula
a passage through the tissues which allows the excess exudate to drain
incision and drainage
surgical procedure for the removal of the excessive exudate
vasoactive factors
histamine seratonin bradykinin LTs/PGs PAF
chemotactic factors
C5a LTB formylated peptides lymphokines monokines
increase vascular permeability
edema
margination
the movement of the white blood cells to the periphery of the blood vessel walls
adhesion or pavementing
the adherence of white blood cells to the blood vessel walls
chemotaxis and emigration
the directed movement of white blood cells to the area of injury by chemical mediators which are called chemotactic factors (chemotaxis) and then the passage of white blood cells through the endothelium and wall of the microciruclation into the injured tissue (emigration)
phagocytosis and intracellular degradation
white blood cells ingest foreign material
extraceullar release of leukocyte producets
granules can release their contents into the tissue causing tissue damage
cellular events in acuste inflammation
1) margination
2) adhesion or pavementing
3) chemotaxis and emigration
4) phagocytosis and intracellular degradation
5) extracellular release of leukocyte products
exudation
neutrophils are the most prominent inflammatory cell in the first few hours (acute inflammation)
cytokines
activator; must be made in the cell –> further inflammation (attracting more cells); systemic effects like fever
prostaglandins
activator; must be made in the cell –> further inflammation; pain (aspirin)
histamine
activator; released from granules –> vasodilation and increased vascular perm. (anti-histamines)
complement
activator; increase in vascular perm.; attacts inflammatory cells; attacks microorganisms
kinins
activator; increase in vascular perm; pain
clotting
activator; coagulation
resolution
involves neutralization or removal of the chemical mediators of actue inflammation with subsequent normalization of vascular permeabiltiy and halting of leukocyte emigration; the combined efforts of lymphatic drainage and macrophage digestion lead to clearance of edema fluid, inflammatory cells and enecrotic debirs, resulting in the restoration of the inflammatory site to histologic and functional normalcy
when does resolution occur
1) the injury is limited or short lived
2) there has been minimal tissue destruction
3) the tissue is capable of regeneration
scarring (fibrosis)
extensive fibrinous exudates that cannot be absorbed are instead organized by ingrowth of connective tissue elements, resulting in a mass of fibrous scar tissue
scarring occurs when
1) inflammation affects tissues that cannot regenerate
2) there has been substantial tissue destruction
abscess formation
occurs in the setting of certain pyogenic bacterial or fungal infections
chronic inflammation
1) infiltration with mononuclear “chronic inflammatory” cells which include macrophages, T lymphocytes, and plasma cells
2) tissue destruction, largely due to the inflammatory cells themselves
3) repair involving new vessel proliferation (angiogenesis) and scarring (fibrosis)
chronic inflammation
inflammation of prolonged duration (months to years) in which active inflammation, tissue injury and healing proceed simultaneously
persistent infections
by a select of microorganisms including mycobacteria (tuberculosis bacilli), trepponema pallidum (syphilis) and some fungi; these are generally organisms of low pathogenicity that evoke delayed hypersensitivity reactions in the host (sometimes leading to a granulomatous reaction)
settings where chronic inflammation arises
1) persistent infections
2) prolonged exposure to toxic agents
3) autoimmune diseases
chronic inflammatory cells
1) tissue macrophages
2) t lymphocytes
3) plasma cells
4) eosinophils
tissue macrophages
originate as monocytes in the blood; they will migrate out to the site of injury 24-48 hours after the onset of acute inflammation, where they are then called tissue macrophages. macrophages specialize in ingesting debris and microorganisms and producing cytokines, important inflammatory mediators that recruit and activate T lymphocytes
T lymphocytes
in turn, will stimulate macrophage activity by producing their own cytokines
plasma cells
B lymphocytes that make antibodies
eosinophils
associated with allergic reactions and parasites
macrophage activation
chemokines, especially RANTES, MCP-1 and MIP-1 are secreted by monocytes, smooth muscle cells and fibroblasts in damagedtissue, which then recruit and activate monocytes and changes their integrin configuration, allowing them to bind VCAMs and ICAms on endothelium and migrate out into the tissues in a manner analagous to neutrophils
lymphokines from T lymphocytes recruit and activate macrophages; activated macrophages increase in size and produce more lysosomal enzymes as well as cytokines and growth factors of their own that influence blood vessel and smooth muscle cell growth; these factors regulate local healing and formation of the final scar
fibrosis
GFs (PDGF, FGF, TGFB)
fibrogenic cytokines
angiogenesis factors (FGF)
remodeling (collagenases)
tissue injury
toxic oxygen metabolites proteases neutrophil chemotractic factors coagulation factors A.A. metabolites nitric oxide
IL-1, TNF-apha acute phase reaction
fever (via PGE) increase sleep decrease appetite, muscle wasting increase acute phase proteins hemodynamic effects (shock) neutrophilia
IL-1, TNF-alpha endothelial effects
increase luekocyte adherence increase PGI synthesis increase PAG increase pro-coagulant activity decrease anti-coagulant acitivyt
IL-1, TNFalpha fibroblast effects
increase proliferation
increase collagenase
increase protease
increase pGE sythesis
systemic manifestations of chronic inflammation
fever
leukocytosis
acute phase response
fever
endogenous pyrogens (IL-1, TNFalpha0
luekocytosis
an increase in the numbers of circulating leukocytes due to release of IL-1, TNFalpha
acute phase response
fever, leukocytosis, decreased appetite, altered sleep patterns, acute phase proteins; increase erythrocyte sedimentation (ESR) reflects higher plasma levels of acute phase proteins
b lymphocytes
terminally differentiate into plasma cells and eisinophils
non-specific inflammation
mononuclear cell infiltrate with a proliferation of fibroblasts and new blood vessels; chronic inflammation can be the initial response in viral infections, parasitic infections, autoimmune disease and malignancy
granulomatous inflammation
characterized by granulomas (collections of activated macrophages called “epithelial cells” surrounded by a rim of lymphocytes, +/- gaint cells); IFNgamma and IL_4 released by T lymphocytes modified macrophages, sometimes resulting in their fusion to form multinucleated giant cells. granulomatous ifnlammation occurs in response to bacterial infections fungal infections, parasitic infections, inorganic metals or dusts, forign body reactions, diseases of uknown cause
stable cells
form tissues that normally are renewed very slowly but are capable of rapid renewal after tissue loss (liver, proximal renal tubules, endocrine glands, endothelium); in these tissues the ability to regenerate depends on the potential to replicate, not the actual number of steady-state mitoses
permanent cells
permanent cells are terminally differentiated and have lost all capacity for regeneration (neurons, cardiac monocytes, cells of the lens)
EGF
mitogenic for epithelial cells and fibroblasts
PDGF
released from platelet alpha granules but is also produced by activated macrophages, endothelial cells, smooth muscle cells and a variety of transformed cells; it induces fibroblast, smooth muscle cell and monocyte migration and proliferation
FGF
made by active macrophages and binds to heparin and other anionic ECM components, so it has a strong affinity for the basement membrane. it strongly promotes angiogenesis.
TGF-beta
made by a many cell types in an active form that needs to be proteolytically cleaved to become functional; it has a variety of effects but generally is growth inhibitory for epithelial cells and promotes fibrinogenesis and scarring - it stimulate fibroblast chemotais and production of collagen and fibronectin and inhibits digestion of the ECM by metalloproteinases
VEGF
there are many isoforms; it is made by tumor cells and promotes angiogenesis and vascular permeability; increased vessel leakiness leads to deposition of plasma proteins, such as fibrinogen, out in the tissues, which provides a provisional stroma for fibroblast and endothelial cell ingrowth
cytokines (IL-1, TNF-aplpha)
chemotactic and mitogenic for fibroblasts, an also induces synthesis of collagen and collagenases
basement membrane
structures that separate epithelial and endothelial cells, schwann cells in the PNS and adipocytes and all types of muscle cellsm from the stroma; it provides polarity and is required for orderly renewal of tissue, particularly epithelieum
collagen
widely represented in the body and has mainly mechanical functions; collagen fibers provide strength and support; there are many types, most of which form strong, triple helical fibers
type I
collagen is the principle collagen of bone, skin, and tendons and the predominant collagen in mature scars
type II
collagen is the major collagen in cartilage
type III
collagen is adbundant in embryonic tissues, blood vessels, uterus and GI tract
type IV
collage in found exclusively in basement membranes
type V-XXII
basement membranes
glycoproteins
a structurally diverse group of proteins whose role is to link ECM components to cells and to one another; these include fibronectin (which binds integrins), laminin (the most abundant protein in the BM), and thrombospondins
proteoglycans
includes glycosaminoglycans like dermatan sulfate and heaprin sulfate that help maintan ECM structure and permeability
fibrosis steps
1) angiogenesis
2) migration and proliferation of fibroblasts
3) deposition of Ecm
4) maturation and organization of the scar
events that occur during healing
induction of acute inflammation following initial injury –> parenchymal cell regeneration (if possible) –> migration and proliferation of parenchyma an connective tissue cells –> synthesis of ECM components –> remodeling of parenchyma and ECM to restore function and increase wound strenght
events that occur during healing day of injury
clot formation
fibrin+
RBCs+
platelets
events that occur during healing day 1
neutrophils
phagocytosis
events that occur during healing day 2
macrophages lymphocytes plasma cells fibroblasts epitheliial cells granulation tissue formation epithelial proliferation and migration
events that occur during healing one week
fibrin digestion initial repair complete inflammation complete granulation tissue formation epithelial proliferation and migration
events that occur during two weeks
scar
healing by primary intention
a clean incision with approximal ends; as a result, epithelial regneration predomintes over fibrosis. little granulation tissue forms and less scar tissue resutls
healing by secondary intention
where cell or tissue loss is extensive (large, ulcer, abscess or open wound); there can be extensive granulation tissue and scarring with a great deal of wound contraction (due to myofibroblasts)
healing by tertiary intention
waiting until an infection is resolved before performing tissue repeair
local factors that influence healing
wound type, size and location
vascular supply
infection
movement
systemic factors that influence helaing
circulatory status
infection
metabloic status
malnutrition
complications of wound healing
deficient scar formation (dehiscence and incisional, hearnias, ulceration); extensive scar formation (hypertrophic scar formation); exxcessive contraction (contractures)
