chronic inflammation

why does acute inflammation proceed to chronic?
acute inflammation becomes chronic if the injurous stimulus isn’t removed. common causes are persistent infections or toxins and autoimmune disease
when does healing occur in relation to chronic inflammation?
they occur simultaneously, a “race to win” though chronic inflammation can overwhelm the healing response and then can dictate whether healing, scarring, or more chronic inflammation occur
what are the histologic features of chronic inflammation?
infiltration of mononuclear cells, tissue destruction, attempts at healing
what are the mononuclear cells that infiltrate in chronic inflammation?
macrophages, lymphocytes, plasma cells, mast cells, and at times, eosinophils. the first do are seen in every kind of chronic inflammation however.
what is a histologic hallmark of chronic inflammation?
tissue destruction due to ROS’s and enzymes are released by WBCs
what are examples of histologic attempts at healing in chronic inflammation?
connective tissue replacement, angiogenesis, and fibrosis
what is the first part of chronic inflammation?
within 48 hours after acute inflammation monocytes move in and predominate (take over from neutrophils)
what do monocytes become once they get to the injured tissue in chronic inflammation?
monocytes from the blood transform in tissues to macrophages in the tissue
what is monocyte migration similar to?
PMN migration in acute inflammation, including integrin interaction, adhesion molecules, rolling, etc
why are macrophages the central player in chronic inflammation?
this is due to the variety of substances they produce
what are the two pathways from the pleuripotential bone marrow stem cell that macrophages/dendritic cells come into being?
1) pleuripotent cell->myelomonocytic stem cells->monohistiocytic lineage->dendritic cells, (eg langerhans) OR 2) pleuripotent cell-> monoblast->promonocyte->monocyte->blood monocyte-tissues>ordinary histiocytes, (pulmonary alveolar macrophages, von kupffer cells, osteoclasts, microglia cells, splenic sinusoidal reticular cells, pleural/perionteal/synovial macrophages, resident tissue macrphages
what are the 3 mechanisms for macrophage accumulation and persistence in chronic inflammation?
recruitment, division and immobilization(many also apoptose after inflammation), (mediated by cytokines)
what are the 3 important products released by macrophages?
enzymes, ROS and cytokines
what are the important macrophage/monocyte inhibitory cytokines?
MIP-1 alpha, MIP-1 beta
what are the important macrophage/monocyte chemotactic cytokines?
what do chemokines do to macrophages in terms of adhesion, calcium, cell migration, extracellular matrix, and pathogen-lysing material?
cytokines can cause macrophages to: activate adhesion molecules, act through G protein-coupled transmembrane receptors & cause Ca++ influx (actin effect), induce haptotaxis, (cell migration), bind to proteoglycans/ECM, and induce oxygen burst/release of proteinases
what are the major features of the chronic inflammatory response?
1)persisting injurious agent (wks+) 2)macrophage+lymphocyte predominant cellular response 3)granuloma formation from prolonged macrophage stimulation 4) tissue necrosis w/ingrowth of fibrovascular granulation tissue, resulting in scar formation.
can persistent neutrophilic exudation be present in chronic inflammation?
yes occasionally
what is the difference between a granuloma and granulation tissue?
a granuloma is where you have macrophages and a lot of debris. granulation tissue is actually the healing reponse to a granuloma/attempt to correct that problem.
what aer 2 stimuli for macrophage activation?
1) an immune mediated process involving activated T cells and 2) a non-immune activation response where the body has been invaded and endotoxin (LPS) production is occuring as well as chemical mediators are being secreted
what are the 2 paths activated macrophages can take?
tissue injury through their secretions or attempting to repair through the fibrosis response, (competing tasks)
what is the cytokine stimulation cycle between macrophages and lymphocytes?
T cells stimuate macrophages with IFN gamma and macrophages stimulate lymphocytes with IL-1 and TNF
what are common causes of reactive monocytosis?
bacterial and parasitic agents, malignant diseases, autoimmune diorders, drug reactions
what is reactive monocytosis?
>10% monocytes in the body
when mycobacterium tuberculosis inhibits phagosome maturation what are the 2 outcomes?
some macrophages still mature and an immunity is able to be mounted OR a delayed hypersensitivity reaction can occur; where cell mediated responses are happening with activated lymphocytes and macrophages acting upon each other to give an area of chronic inflammation, leading to cell damage/tissue destruction that is the granuloma
why are active macrophages called “epitheliod”?
they become enlarged with protein and ROS and take on an epithelia cell appearance
why does do parts of a granuloma appear pink?
collagen and fibrin split products appear pinkish
what are fibrin split products?
in granulomas, you have angiogenesis is trying to bring in new blood vessels, you also have a clotting response, (keep bleeding down), and lastly you have fibrinolysis, (digestion of the clot). the products of fibrin being made and then chewed up leaks out and associates with the collagen being made in the tissues and thats why you see them as pink when stained with eosin
what do you see in granulomas that have been long standing?
lack of T cells and healing response wants to take over but it has become pathologic healing
what are giant cells? how to the nuclei appear?
fusions of macrophages that become multi-nucleated giant cells. the nuclei appear as horshoes in “langhans” giant cells -> often seen in TB, sometimes in sarcoidosis
what would be likely confirming in a sputum sample for TB?
langhans giant cells and acid-fast mycobacteria showing up in a stain, (chest x ray would also be done)
why does mycobacterium leprae just infect the skin?
the skin temperature is lower then the core temperature which the bacteria prefer, (unlike mycobacterium tuberculosi_
what is an example of a foreign body that can cause granuloma formation?
methyl-methacrylate: used to be used to cement in hip replacements
what kinds of giant cells do you see with foreign body granuoma formation?
“foreign body giant cells”
what are the key categories of causes for granulomas?
bacterial origin, (TB, leprosy), fungal origin, helminthic origin, metal induced, unknown, (sarcoid/crohn’s/wegener’s granulomatosis), some cancers
what is undifferentiatable from TB via xray? what is seen in both?
sarcoidosis, enlargement of perihilar lymph nodes
what happens in chron’s disease?
inflammation of the large intestine, leading to destruction of the epithelial layer, therefore granulomas form
what do glucocorticoids do in terms of chronic inflammation?
glucocorticoids suppress CD4 cells, stimulate apoptosis of eosinophils, inhibit expression of adhesion molecules/receptors, decrease transcription rates for IL-1+6, suppress phospholipase A2, COX-2 and NO synthetase
how can TGF-beta be used to treat chronic inflammation?
it is an antagonist to IL-1, TNF and INF-gamma
what do pentoxifylline and thalidomide do in terms of chronic inflammation?
suppress the release of TNF-alpha from phagocytes, (one of the most damaging cytokines in CA, causes cachexia)
what does infliximab do in terms of chronic inflammation?
infliximab is a monoclonal antibody to TNF-alpha that blocks the protein’s antibody. (there is a risk of developing lymphomas)
what are the sequelae following tissue damage/loss?
resolution, regeneration, repair
what happens in resolution phase of tissue damage/loss? when does this occur?
dead cells/debris are phagocytized and orginal tissue architecture is left intact. this occurs when there is little tissue destruction, eg lobar pneumonia where early states result in pus filling the alveolar paces, but without destroyng the alveolar walls. with the proper treatment and clearance by macrophages, the spaces clear w/no damage to the alveolar walls
what happens in regeneration phase of tissue damage/loss? when does this occur?
proliferation of cells replaces lost tissue and normal architecture is reconstructed. 2 aspects are considered: 1) cell types 2) tissue architecture 3) amount of tissue loss
what happens in regeneration phase of tissue damage/loss, what are the cell types considered?
labile: cells w/a high rate of loss and replacement, (eg. squamous epithelia and bone marrow hematopoietic cells), these have a high replacement capacity. stabile: these do not normally proliferate to a great extent, but can after damage, (eg hepatocytes, osteoblasts, endothelia, fibroblasts, and renal tubule cells) permanent: inability to divide after development and differentiation – cannot regenerate, (eg CNS neurons)
what happens in regeneration phase of tissue damage/loss, what are the tissue structures considered?
simple structures regenerate better than complex ones, (liver regnerates better than the pancreas or kidneys). there are clinical consequences of imperfect regeneration, (eg. chronic inflammation of liver results in much hepatocyte proliferation, but w/damage to the connective tissue). regenerated tissue produces an abnormal nodular architecture, (eg. cirrhosis, which can result in the hemodynamic abnormalities in the hepatic portal venous system giving portal HTN, hemmorrhage, death)
what happens in regeneration phase of tissue damage/loss, what are considerations for amount of tissue loss?
with large areas of tissue loss, scar formation will outweigh the regenerative capacity, eg. with a large ulceration or skin wound, the rater of epidermal cell migration lags behind scar formation
what happens in repair phase of tissue damage/loss? what do you see going on here?
fibrous scar produced from granulation tissue replaces lost tissue. this is where you see angiogenesis, macrophages chewing up material, fibroblast activation, (these lay down elastin/collagen)
what is wound healing a continuum between? does it wait for inflammation to subside?
pathologic states of repair and ineffective healing. it does not wait for inflammation to subside
do all tissues have the same characteristic paths of repair cascade?
no, different tissues have their own characteristic paths
what are the early/organization steps of the repair process?
macrophages try to remove necrotic debris and foreign material. endothelial cells and fibroblasts proliferate and endothelial cells grow into the damaged area. this is where the production of granulation tissue is begun.
what forms granulation tissue?
the loose connective tissue framework is created by capillary formation and fibroblast migration
why does a mature scar stain bluer than granulation tissue?
mature scars are dense with collagen that stains blue, there is less collagen in granulation tissue
how do arterioles and venules begin to form in granulation tissue?
capillary vessels anastomose to establish blood circulation in the area of healing. vessel differentiation between arterioles and venules occurs
why do fibroblasts begin producing collagen in granulation tissue?
fibroblasts begin producing collagen to give tissue tensile strength
what does the mature scar consist of? how does the volume of the scar compar to the amount of original tissue replaced?
dense collagen. the volume of the scar is always less than the amount of original tissue it has replaced.
what are clinical implications of scarring?
scar contraction and loss of function esp around joints, (contractures form particularly with burns)
what is one way that the entire procedure of repair is regulated? what are the steps of this regulatory process? what does this depend on?
neovascularization/angiogenesis regulates the repair process, where preexisting vessels bud or sprout to make new vessels, (it happens in this sequence: 1)proteolysis of parent vessel membrane 2) migration of endothelial cells toward stimulus 3)proliferation of endothelial cells beyond migrating edge 4) maturation of endothelial cells and remodeling into tubes 5) recruitment of pericytes, smooth muscle cells). all of these steps depend on vascular cells, growth factors, and extracellular matrix interactions
what are the growth factors present in regulation of the repair process?
VEGF, TGF-beta, TGF-alpha, PDGF, EGF, FGF, TNF-alpha, IL-1
what is VEGF? what secretes it? what induces it? what are its functions? is it soluble?
vascular endothelial growth factor. it is a dimeric glycoprotein in a family of VEGF, VEGF-B, C and placental growth factor, (PGF). it is secreted by mesenchyma and stromal cells, but receptors are confined to endothelial cells. it is induced by hypoxia, TGF-beta, PDGF, and TGF-alpha. it functions to promote angiogenesis, endothelial cell migration and proliferation, and increase vascular permeability. it is soluble. *VEGF-C selectively induces hyperplasia of lymphatic vessels.
what is TGF-beta? what is it made by? what are its functions?
transforming growth factor beta is a homodimeric protein with 3 major isoforms, -beta 1,2,3. it is made by platelets, endothelial cells, lymphocytes and macrophages. it functions to promote monocyte chemotaxis, fibroblast migration, collagen synthesis and inhibits: collagenase secretion – ** want this for proper healing
what is PDGF? what receptors does it bind to? where is it stored? what is it produced by? what are its functions?
platelet derived growth factor has 2 dimers: A&B, and 3 isoforms: AA,AB,BB. it binds to alpha and beta receptors and is stored in platelets in alpha granules and released upon activation. it is produced by activated macs, endos, sm muscle and tumor cells. its functions include: promotion of monocyte chemotaxis, fibroblast migration+proliferation, collagen sythesis+secretion. ** it is similar to TGF-beta, but it also secretes collagenase
what is EGF? what does it bind? what other growth factor is it similar to? where is it distributed? what are its functions?
epidermal growth factor binds to cERB1 receptor, (has tyrosine kinase activity), has extensive homology with TGFalpha, which produces the same effects. it is distributed in tissue secretions, (sweat, saliva, urine, intestinal contents) and it functions to promote fibroblast migration and proliferation. it has a discovered ability to promote precocious tooth eruption
what is FGF? what does it associated/bind with? what are its functions? what is it importatant in? when is it made?
fibroblast growth factor comes in acidic, (FGF1) and basic, (FGF2) forms. it associates/binds to heparin sulfate proteoglycans in ECM and serves as a reservoir for local cell proliferation. bound receptors have intrinsiv tyrosine kinase activity. it functions to promote monocyte chemotaxis, fibroblast migration/proliferation, angiogenesis, and collagenase secretion. **it is important in new blood vessel formation, wound repair, development and hematopoiesis. it is made all the time and stays in the ECM, which when damaged lets FGF start binding to cells and activates them and healing process.
what do TNF alpha and IL-1 do?
promote migration and proliferation of fibroblasts in granulation tissue
what are some extracellular matrix proteins involved with regulation of the repair process?
proteoglycans, alpha/beta integrins, matricellular proteins, and proteases
what are some proteoglycan ECM matrix proteins involved in regulation of the repair process?
proteoglycans: heparin sulfate, chondroitin sulfate, (inhibitor in adult brain cell regeneration – nerve sprouts cannot break through it, but it allows it in developmental stages) dermatan sulfate.
what do proteoglycan ECM matrix proteins alpha/beta integrins do in regulation of the repair process?
alpha/beta integrins are critical for maintaining new blood vessels – they interact with the proteoglycans
what do proteoglycan ECM matricellular proteins do in regulation of the repair process?
matricellular proteins such as thrombospondin 1/tensacin C destabilize the cell-matrix interactions to promote angiogenesis
what do proteoglycan ECM matricellular proteases do in regulation of the repair process?
proteases such as plasminogen activators and matrix metalloproteases are important in remodeling during endothelial cell invasion
what is syndecan?
a cell surface protein that binds heparin sulfate that binds free FGF, and can bring it to FGF recepotors
at a site of energy what has to happen so cells can become moremotile? how is the signal for this given?
the cytoskeletal matrix has to be broken down, integrins help with the signalling process so that this will occur
what is fibrosis? what is the most important cytokine in this process? where do you see fibrosis?
a component of fibroblast proliferation leading to high levels of collagen being deposited in an area of damage. TGF beta is the most important factor in this process as it inhibits breakdown of collagen, (this and other growth factors promote migration/proliferation to site of injury). fibrosis is seen in chronic fibrotic diseases.
what are fibrotic diseases? when are they seen?
where the level of collagen deposited has been overshot, often seen in chronic diseases
what is the first step of fibrosis?
fibroblast proliferation where growth factors promote migration and proliferation of fibroblasts to the site of injury, (TGF beta being the most of which)
what is the second step of fibrosis? what will happen to the number of fibroblasts/endothelial cells? what kind of collagen is deposited in this phase?
extracellular matrix deposition. with ongoing repair, the level of fibroblasts/endothelial cells drops. fibrillar collagen, (types 1-3) are made at this time, which are important for wound strength. growth factors are important here.
what is net collagen accumulation?
a function of collagen synthesis + collagen degradation
what is the next step in fibrosis after extracellular matrix deposition? what replaces granulation tissue in this step? what happens in this step and how is it regulated?
tissue remodeling where granulation tissue is replaced with a scar. matrix metalloproteinases, (Zn++ dependent ushc as interstitial collagenases, gelatinases, and stromelysins) degrade collagen and other ECM proteins. matrix metalloproteinases are rapidly inhibited by tissue inhibitors of metalloproteinase, (TIMPs)
what factors stimulate collagenases?
what factors inhibit collagenases?
TGF beta, steroids
what are the processes of wound healing?
induction of inflammation from injury, regeneration of parenchymal cells (major cells of the tissue), migration/proliferation of parenchymal cells and connective tissue cells, synthesis of ECM, remodeling, collagenization and increased wound strength
what is wound healing by first intention? what marks the way the wound is created?
wounds with opposed edges. this is marked by death of epithelial/connective tissue cells, basement membrane disruption and a blood clot filled with fibrin & blood cells forming a scab upon dehydration
what happens in the first 24 hrs of wound healing by first intention?
PMNs are at margins, they migrate to the clot. the epidermis thickens at the cut edge and the mitotic activity of the basal cells is increased
what happens in the first 24-48 hrs of wound healing by first intention?
the epithelial spurs migrate and grow along cut margins of the dermis, the basement membrane is laid down, and the epithelial cells fuse at midline
what happens by day 3 of wound healing by first intention?
PMNs are replaced by macros, granulation tissue invades incision space and vertically oriented collagen fibers appear at margins – the epithelial cell layer thickens
what happens by day 5 of wound healing by first intention?
the space is filled with granulation tissue, max neovascularization is reached, more abundant collagen fibrils begin to bridge the incision, and the epidermis obtains normal thickness – the surface differentiates to normal architecture and keratinization
what happens by the second week of wound healing by first intention?
the collagen begins to accumulate, fibroblasts continue to proliferate. leukocytes infiltrate, increased vessels have disappeared, and blanching begins
what happens by the end of the first month of wound healing by first intention?
the scar makes up cellular connective tissue, no inflammatory cells, the wound is completely covered by intact epidermis and the dermal appendages in the incision line are permanently lost – tensile strength increases, (**max strength may take months to achieve)
what is wound healing by second intention? how is it different than first intention wound healing?
a second intention wound represents a large tissue defect that must be filled, as parenchymal cells cannot completely fill, abundant granulation tissue grows in from the margins. the inflammatory reaction to second intention is more intense, (more necrotic debris/exudate to be removed), larger amounts of granulation tissue are formed, and wound contraction may be seen in large surface wounds due to the presence of myofibroblasts
what is primary or secondary intention wound healing determined by?
the nature of the wound, (not the healing process)
upon removal of sutures at the end of the first week, what % of the strength of unwounded skin is the wound?
over the next 3 wks, what % of the strength of unwounded skin is the wound?
at the fourth month, what % of the strength of unwounded skin is the wound?
60%, (rate slows at third month)
at 6-12 months, what % of the strength of unwounded skin is the wound?
80% -> mature scar
what are local factors influencing wound healing?
persistent infection/foreign material, inadequate blood supply, excessive movement, irradiation, locally applied drugs such as corticosteroids
what are systemic factors influencing wound healing?
age, (healking slower/less effective with increasing age), nutritional deficiencies, metabolic disease (renal failure/diabetes), catabolic state associated with malignancy, systemic drugs (eg corticosteroids)
what is the tissue specific healing response of bone? what can repair be manipulated by?
bone heals without scarring, remodeling occurs in response to mechanical stress and normal/near normal strength is achieved. repair can be manipulated by electrical stimulation, growth factors, and distraction osteogenesis, (bone lengthening)
what is the tissue specific healing response of intestine? what does a local infection do? what are adhesions?
anastaomosis regains strength rapidly, much collagen lysis occurs. if there is a local infection, lysis is promoted and collagen resynthesizes, increasing the chance of perforation. adhesions are almost an inevitable consequence, promoted by ischemia/abscesses/foreign bodies, all attract macrophages, leading to the fibrotic process – the peritoneum produces plasminogen factor to cleave fibrin and decrease adhesion occurence.
what is the tissue specific healing response of nerves?
in CNS, connective tissue scar formation from glia, perivascular cells, and fibroblasts. in the PNS, distal severed nerve degenerates, though axons can regenerate through neural sheaths, but reconnecting may be random
what are pathologic aspects of wound repair?
deficient scar formation, excessive formation of the repair components, and contracture formation
what 2 things happen in deficient scar formation?
wound dehisecence, (rupture) or ulceration
what are problems with excessive formation of the repair components?
accumulation of excessive collagen, (keloid/hypertrophic scar – more common w/darker skin), excessive granulation tissue, (exuberant granulation/proud flesh), or exuberant proliferation of fibroblasts, (desmoids or aggressive fibromatoses) – may be hyperplases or neoplasia
what is contracture formation?
an exaggeration of normal contraction of wound, palms/soles, anterior aspect of thorax all prone, often seen after serious burns
what does chronic inflammatory fibrosis involve? (ex. RA, lung fibrosis, hepatic cirrhosis)
leukocyte-macrophage interaction maintaining the damage-repair scenario
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