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94 Cards in this Set
- Front
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Regeneration
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structural and functional
`` restitution of `` `` injured tissue |
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Repair by scar formation and fibrosis –
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repair of injured tissue by
`` fibrous connective tissue Scarring/fibrosis restores `` structure/continuity `` but not `` `` function of injured tissue |
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The goal of the repair process is to
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restore the tissue to its
`` original state with `` `` complete restitution of `` `` `` structure and `` `` `` function `` `` `` (regeneration) |
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When restitution of parenchymal mass cannot occur,
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the injured tissues are
`` `` “welded” together by `` `` `` fibrous connective tissue `` `` `` (scarring/fibrosis |
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Regeneration
Urodele amphibians such as newts can regenerate their tails, limbs, lens, retina, jaws and even a large portion of the heart This remarkable regenerative capacity has been attributed to two main factors: |
the capacity of
`` quiescent cells such as `` `` cardiac myotubes `` to reenter the cell cycle, efficient differentiation of `` `` stem cells `` in the area of injury Such capacity for regeneration of `` whole tissues and organs `` `` has been `` lost in mammals |
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Regeneration
The inadequacy of true organ regeneration in mammals has been attributed to |
the rapid
`` `` fibroproliferative response `` `` and scar formation after wounding |
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Regeneration
The regenerative capacities of mammalian tissues are |
quite variable;
`` in general, `` `` the more specialized the tissue is, `` `` `` `` the more limited the capacity to regenerate exists |
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Stimulus for regeneration
Social Order |
Primary tissue culture cells grow in Petrie dish until
`` they create a confluent monolayer `` at which time `` `` migration and mitosis is usually down regulated Similarly, normal cells in virtually any tissue create `` an orderly mosaic characteristic for that tissue, `` `` not crowding one another and `` `` not exceeding the overall space allotted to the tissue or organ within body There is likely a multitude of `` `` overlapping and `` `` redundant `` regulatory messengers responsible for this `` ``` “social order” within tissue These chemical messengers are `` `` growth factors and `` `` cytokines `` that `` `` stimulate or `` `` inhibit `` cell proliferation of `` `` normal and `` `` injured tissue Accordingly, within hours of tissue injury, `` viable parenchymal cells at the periphery of the lesion `` undergo `` `` biochemical and `` `` morphological alterations `` that clearly indicate `` `` “their awareness” of the `` `` `` adjacent necrosis `` `` `` and the need for regenerative activity This is achieved by `` binding of `` `` released growth factors/cytokines to `` `` `` cellular receptors `` with consequential intercellular signaling `` `` “cellular communication |
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Stimulus for regeneration
Social Order Intracellular Signalling 3 Systems |
Autocrine signaling:
`` Cells respond to the signaling molecules that `` `` they themselves secrete, `` thus establishing an autocrine loop `` Several `` `` polypeptide growth factors and `` `` cytokines `` act in this manner Paracrine signaling: `` One cell produces the ligand, `` which then acts on the `` `` adjacent target cells that `` `` `` express the appropriate receptors `` The responding cells are `` `` in close proximity to `` `` `` the ligand-producing cell `` `` and are generally of a `` `` `` different type `` Paracrine stimulation is common in `` `` connective tissue repair of healing wounds, `` `` `` in which a factor produced by one cell type `` `` `` `` (e.g., a macrophage) `` `` `` has its growth effect on adjacent cells `` `` `` `` (e.g., a fibroblast Endocrine signaling: `` Hormones are synthesized by `` `` cells of endocrine organs `` and act on target cells `` `` distant from their site of synthesis, `` being usually carried by the blood ``Several cytokines, `` `` such as those associated with `` `` `` the systemic aspects of inflammation `` `` `` `` IL-1, `` `` `` `` TNF `` also act as endocrine agents |
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Requirements for regeneration
Regeneration will occur only if all of the following requirements are present: 4 |
Debridement
Tissue Scaffold Available Blood Supply Surviaval of Germinal Cells If any of these is missing, `` regeneration will not happen, `` instead, `` `` scarring and `` `` fibrosis `` will take place |
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Requirements for regeneration
Debridement is |
the removal/clearing of
`` necrotic tissue by `` `` sloughing `` `` `` (necrotic epithelium) `` or by `` `` inflammatory infiltration of phagocytes `` `` `` neutrophils and `` `` `` especially macrophages) |
|
Requirements for regeneration
Tissue scaffold |
Parenchymal cells require a
`` scaffold `` `` (supporting stroma) `` upon which to grow The normal scaffold consists of `` the basement membrane `` and extracellular matrix `` `` collagen, `` `` elastic fibers, `` `` proteoglycans, `` `` fibroblasts etc Some viral and toxic injury destroy `` `` only epithelial or `` `` parenchymal cells `` but not supporting stroma `` `` allowing complete regeneration `` `` `` if animal survives In contrast, `` `` ischemic necrosis or `` `` bacterial infections `` tend to damage `` `` non-selectively `` `` `` all components of affected tissue `` tf usually repaired by `` `` fibrosis/scarring |
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Requirements for regeneration
Available blood supply |
Obviously,
`` adequate nutritional supply is `` `` necessary for regeneration Destruction of scaffolding is `` usually associated with `` `` destruction of blood supply as well |
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Requirements for regeneration
Survival of germinal cells |
Survival of cells capable of motosis is
`` an absolute prerequisite `` `` for tissue regeneration |
|
Tissue-proliferative activity
The tissues of mammals are divided into three groups on the basis of their proliferative activity: |
labile tissues
stable tissues permanent tissues |
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Tissue-proliferative activity
Labile tissues |
In labile tissues
`` `` (tissue with continuously dividing cells) `` cells proliferate `` `` throughout life, `` replacing those that are lost Mature cells of most labile tissues are `` derived from stem cells, `` `` which have an `` `` `` unlimited capacity to proliferate `` `` and whose progeny may `` `` `` undergo various streams of `` `` `` `` differentiation Surface epithelia: o Stratified squamous epithelium `` `` `` `` skin, `` `` `` `` oral cavity, `` `` `` `` vagina o Mucosal epithelium `` `` `` columnar epithelium of `` `` `` `` gastrointestinal tract `` `` `` `` uterus, `` `` `` transitional epithelium of `` `` `` `` urinary tract, `` `` `` epithelium of `` `` `` `` glandular ducts Hematopoietic tissues |
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Tissue-proliferative activity
Stable tissues |
Stable (or quiescent) tissues normally have
`` `` a low level of replication; `` however, cells from these tissues can `` `` undergo rapid division `` in response to stimuli `` and are thus capable of `` `` reconstituting the tissue of origin The regenerative capacity of stable cells is `` best exemplified by the ability of `` `` the liver to regenerate after partial hepatectomy Parenchymal cells in `` `` liver, `` `` kidneys, `` `` pancreas Mesenchymal cells: `` `` fibroblasts, `` `` vascular endothelial cells, `` `` chondrocytes, and `` `` osteocytes |
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Tissue-proliferative activity
Permanent tissues |
Permanent tissues
`` contain non-dividing cells that `` `` cannot undergo mitotic division `` `` `` in postnatal life To this group belong `` `` neurons and `` `` cardiac muscle cells `` `` `` may have limited ability If neurons in the central nervous system are destroyed, `` the tissue is replaced by `` `` the proliferation of the central nervous system supportive elements `` `` `` the glial cells `` `` `` (forming glial scar) If myocardial infarction occurs, `` it will be followed by `` `` scar formation if `` `` `` animal survives |
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Morphological events of epithelial regeneration
3 |
Epithelial sliding
`` `` (attenuated epithelium) `` along a `` `` preexisting basement membrane or `` `` a provisional matrix `` `` `` fibrin or `` `` `` fibronectin `` occurs within `` `` minutes or `` `` hours `` of the initial loss of epithelial continuity Cellular proliferation `` follows `` `` epithelial sliding `` to repopulate `` `` lost epithelial cells Maturation and normalization `` takes sometimes `` `` several weeks Re-establishment of cell-matrix adhesion might `` be initially weak and fragile `` `` (e.g in eroded and healed cornea) |
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Examples of regeneration
5 |
Corneal epithelial erosions
`` have potential for `` `` complete regeneration. Atrophy of small intestinal villi `` `` induced by porcine corona virus `` is completely regenerated if `` `` piglet survives Epithelial vesicles and erosion `` `` on bovine tongue `` `` `` in foot and mouth disease `` will completely regenerate if `` `` not invaded by bacteria Regeneration of skeletal myocytes `` `` affected by white muscle disease i `` s complete if `` `` VitE/Se deficiency is corrected Compensatory hepatic hyperplasia `` In rodents, removal of approximately 70% of the liver `` `` (partial hepatectomy) `` elicits a growth response known as `` `` liver regeneration `` Hepatocytes in the remaining portion of the liver `` `` rapidly proliferate `` and the hepatic mass of the original liver is `` `` reached in 10 to 14 days `` Restoration of liver mass is achieved `` `` without the regrowth of the `` `` `` lobes that were resected at the operation `` Thus, the end-point of liver regeneration after partial hepatectomy is `` `` the restitution of functional mass `` rather than form `` More than 70 genes are activated during this comples response `` Although much has been learned about `` `` the steps that regulate hepatocyte replication, `` the mechanisms of growth cessation have `` `` not been well-established |
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REPAIR BY SCAR FORMATION AND FIBROSIS
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With a few exceptions
`` `` that heal exclusively by regeneration, `` majority of injuries in veterinary medicine will heal `` `` with various degree of scarring/fibrosis Sometimes as early as `` `` 24-48 hours after injury, `` if regeneration `` `` did not occur, `` fibroblasts and vascular endothelial cells begin `` proliferating to form `` `` a specialized type of tissue called `` `` granulation tissue |
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REPAIR BY SCAR FORMATION AND FIBROSIS
Granulation Tissue |
The term derives from its
`` `` pink, `` `` soft, `` `` granular `` appearance on the surface of wounds, histologic features are characteristic: `` the formation of new small blood vessels `` `` (angiogenesis) `` and the proliferation of fibroblasts These new vessels are `` `` leaky, `` allowing the passage of `` `` proteins and `` `` red cells `` into the extravascular space Thus, new granulation tissue is `` edematous |
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REPAIR BY SCAR FORMATION AND FIBROSIS
Angiogenesis What How |
The process of blood vessel formation
`` `` in adults `` is known as `` `` angiogenesis or `` `` neovascularization until recently, `` has been thought to depend on `` `` the branching and `` `` extension of `` adjacent blood vessels Recent work has demonstrated that `` angiogenesis can also occur by `` `` recruitment of endothelial progenitor cells `` `` `` from the bone marrow |
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REPAIR BY SCAR FORMATION AND FIBROSIS
Angiogenesis from pre-existing vessels: 6 Steps |
Vasodilation
`` `` (induced by NO) `` increased permeability `` `` (induced by VEGF) `` of vessels Degradation of `` vascular basement membrane by `` `` proteases Migration of `` endothelial cells towards `` `` angiogenic stimulus Proliferation of `` endothelial cells Maturation of `` endothelial cells and `` `` remodeling into `` `` `` capillary tubes Recruitment of `` periendothelial cells `` `` pericytes, `` `` smooth muscle cells `` to support the `` `` endothelial tubes and `` form the mature vessel |
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REPAIR BY SCAR FORMATION AND FIBROSIS
Scar formation Three processes that participate in the formation of a scar: |
emigration and proliferation of
`` fibroblasts `` `` in the site of injury deposition of `` extracellular matrix `` `` (ECM) tissue remodeling |
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REPAIR BY SCAR FORMATION AND FIBROSIS
Scar formation Fibroblast migration and proliferation |
Granulation tissue contains
`` numerous newly formed blood vessels VEGF promotes `` `` angiogenesis `` but it is also responsible for `` `` a marked increase in vascular permeability The latter activity leads to `` `` exudation and `` `` deposition `` of plasma proteins, `` `` such as fibrinogen and `` `` plasma fibronectin, `` in the ECM `` and provides a `` `` provisional stroma for `` `` `` fibroblast and `` `` `` endothelial cell `` `` ingrowth Migration of fibroblasts to `` the site of injury and `` `` their subsequent proliferation `` are triggered by `` `` multiple growth factors `` `` `` TGF-β, (trans) `` `` `` PDGF, (platelet derived) `` `` `` EGF, (epidermal) `` `` `` FGF, (fibroblaast) `` `` `` and the cytokines `` `` `` `` IL-1 and `` `` `` `` TNF |
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REPAIR BY SCAR FORMATION AND FIBROSIS
Scar formation ECM deposition and scar formation |
As repair continues,
`` the number of `` `` proliferating endothelial cells and `` `` fibroblasts `` decreases Fibroblasts progressively deposit `` increased amounts of ECM Fibrillar collagens form `` a major portion of the `` `` connective tissue in `` `` `` repair sites `` and are important for `` `` the development of `` `` `` strength in `` `` `` `` healing wounds Many of the same growth factors that regulate `` `` fibroblast proliferation `` also stimulate ECM synthesis Ultimately, `` the granulation tissue scaffolding is `` `` converted into a scar composed of `` `` `` spindle-shaped fibroblasts, `` `` `` dense collagen, `` `` `` fragments of elastic tissue, `` `` `` and other ECM components As the scar matures, `` vascular regression continues, `` eventually transforming the richly vascularized `` `` granulation tissue `` into a `` `` pale, `` `` avascular `` `` contracted `` scar |
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REPAIR BY SCAR FORMATION AND FIBROSIS
Scar formation Tissue remodeling |
The replacement of
`` `` granulation tissue with `` a scar involves `` `` transitions in the `` `` `` composition of the ECM Some of the growth factors that `` stimulate synthesis of `` `` collagen and `` `` other connective tissue molecules `` also modulate `` `` the synthesis and `` `` activation of `` `` `` metalloproteinases, `` enzymes that degrade these ECM components The balance between `` `` ECM synthesis and `` `` degradation `` results in `` `` remodeling of the connective tissue framework |
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Cutaneous wound healing
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Although most skin lesions
`` `` heal efficiently, `` the end product may `` `` not be functionally perfect Epidermal appendages do not `` `` regenerate `` and there remains a `` `` connective tissue scar In very superficial wounds, `` the epithelium is reconstituted `` and there may be little scar formation |
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Cutaneous wound healing
Cutaneous wound healing is generally divided into three phases: |
inflammation
`` early and `` late granulation tissue formation and reepithelialization wound contraction, ECM deposition, and remodeling |
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Cutaneous wound healing
Skin wounds are classically described to heal by |
primary or secondary intention
This distinction is based on `` the nature of the wound `` rather than the healing process itself |
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Cutaneous wound healing
Healing by first intention |
(wounds with opposed edges)
Wound healing by first intention is the healing of `` `` a clean, `` `` uninfected surgical incision `` approximated by surgical sutures The incision causes `` death of a limited number of `` `` epithelial and `` `` connective tissue cells `` as well as disruption of `` `` epithelial basement membrane continuity The narrow incisional space `` immediately fills with `` `` clotted blood containing `` `` `` fibrin and `` `` `` blood cells dehydration of the surface clot `` forms the scab that covers the wound |
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Cutaneous wound healing
Healing by first intention The healing process follows a series of 6 sequential steps: |
Within 24 hours,
`` neutrophils are at the margins of the incision, `` moving toward the fibrin clot In 24 to 48 hours, `` spurs of epithelial cells `` `` move from the wound edges `` `` `` with little cell proliferation `` `` along the cut margins of the dermis `` They fuse in the midline beneath the surface scab, `` `` producing a continuous but thin `` `` `` epithelial layer that `` `` `` `` closes the wound By day 3, `` neutrophils have been `` `` largely replaced by macrophages `` Granulation tissue `` `` progressively invades the incision space `` Epithelial cells proliferate By day 5, `` the incisional space is `` `` filled with granulation tissue `` Collagen fibrils become `` more abundant and `` begin to bridge the incision `` The epidermis recovers its `` `` normal thickness, `` and differentiation of surface cells yields `` `` a mature epidermal architecture During the second week, `` there is continued `` `` accumulation of collagen and `` `` proliferation of fibroblasts `` The `` `` leukocytic infiltrate, `` `` edema, and `` `` increased vascularity `` have largely disappeared The long process of `` accumulation of collagen `` `` within the incisional scar `` and regression of vascular channels continues By the end of the first month, `` the scar is made up of `` `` a cellular connective tissue covered by `` `` intact epidermis ``The dermal appendages that have been destroyed in the line of the incision are `` `` permanently lost `` Tensile strength of the wound `` `` increases thereafter, `` `` `` but it may take `` `` `` `` months `` `` for the wounded area to obtain `` `` ``its maximal strength |
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Cutaneous wound healing
Healing by second intention |
(wounds with separated edges)
Healing by second intention is characterized by `` more extensive loss of `` `` cells and `` `` tissue, `` as in surface wounds that create large defects `` the reparative process is `` `` more complicated. Regeneration of parenchymal cells `` `` cannot completely restore the original architecture, `` and hence `` `` abundant granulation tissue grows `` `` `` in from the margin `` to complete the repair |
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Cutaneous wound healing
Differences between healing by first and second intention: 3 |
Large tissue defects
`` generate a larger fibrin clot `` `` that fills the defect `` and more `` `` necrotic debris and `` `` exudate `` that must be removed `` Consequently the inflammatory reaction is `` `` more intense Much larger amounts of granulation tissue are formed Substantial scar formation `` and thinning of the epidermis |
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Wound strength
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At the end of the first week,
`` wound strength is `` `` approximately 10% that of unwounded skin, `` but strength increases rapidly over `` `` the next 4 weeks Approximately thee months after the original incision, `` the wound reaches a `` `` plateau at about `` `` `` 70% to 80% `` of the tensile strength of unwounded skin The tensile strength results from `` the excess of `` `` collagen synthesis `` over `` `` collagen degradation `` and from `` `` structural modifications of collagen fibers |
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Complications in wound healing
5 |
Deficient Scar formation
Excessive formation of Repair components Fibrinous `` pleuritis `` peritonitis `` pericarditis Circumfrential Chrinic Ulceration Hepatic Cirrhosis |
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Complications in wound healing
Deficient scar formation |
Deficient scar formation
`` Inadequate formation of `` `` granulation tissue `` `` or assembly of a scar `` can lead to two types of complications: `` `` wound dehiscence `` `` ulceration |
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Complications in wound healing
Excessive formation of the repair components |
Excessive formation of the repair components
`` Formation of excessive amounts of `` `` granulation tissue, `` `` `` which protrudes above the level of the surrounding skin and `` `` blocks re-epithelialization `` This has been called `` `` exuberant granulation `` `` `` (or proud flesh) `` in horses. |
|
Complications in wound healing
Fibrinous pleuritis, peritonitis, and pericarditis |
Fibrinous pleuritis, peritonitis, and pericarditis
`` often heal through scar formation, `` `` creating adhesions between the `` `` `` visceral and parietal layers of these tissues `` The development of a dense, fibrous scar in the pericardium `` `` can lead to a serious condition called `` `` `` constrictive pericarditis |
|
Complications in wound healing
Circumferential chronic ulceration |
Circumferential chronic ulceration
`` with subsequent fibrosis of a tubular organ `` can cause `` `` constriction. |
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Complications in Wound Healing
Hepatic cirrhosis – |
Hepatic cirrhosis –
`` often fatal by virtue of `` `` progressive downward spiral of injury: `` `` `` fibrosis, `` `` `` ischemia, `` `` `` necrosis, `` `` `` hepatocellular proliferation, `` more fibrosis, `` more ischemia, `` more necrosis and `` more hepatocellular proliferation. |
|
Wound Healing
Growth factors 5 |
There is a large number of known growth factors that
`` stimulate cell proliferation `` and are involved in would healing. Epidermal Growth Factor (EGF) `` is mitogenic for a variety of `` `` epithelial cells, `` `` hepatocytes, and `` `` fibroblasts `` It is widely distributed in tissue secretions and fluids, such as `` `` sweat, `` `` saliva, `` `` urine, and `` `` intestinal contents Vascular Endothelial Growth Factor (VEGF) `` is a potent inducer of blood vessel formation in early development `` `` (vasculogenesis) `` and has a central role in `` `` the growth of new blood vessels `` `` (angiogenesis) `` in adults `` It promotes angiogenesis in `` `` tumors, `` ` chronic inflammation, `` `` and healing of wounds Platelet-Derived Growth Factor (PDGF) `` is stored in platelet α granules `` and is released on platelet activation `` It can also be produced by `` `` macrophages, `` `` endothelial cells `` `` etc `` PDGF causes `` `` migration and `` `` proliferation `` of `` `` fibroblasts, `` `` smooth muscle cells, and `` `` monocytes Fibroblast Growth Factors (FGF) (>10 members) `` have a large number of functions, `` `` in addition to those involved in wound healing `` migration of `` `` macrophage, `` `` fibroblast, `` `` endothelium and `` `` epidermis Transforming Growth Factor β (TGF-β) `` has multiple and often opposing effects `` depending on `` `` the tissue and `` `` the type of injury: `` growth inhibitor for most `` `` epithelia and `` `` leukocytes; `` generally stimulates `` `` proliferation and `` `` chemotaxis `` of fibroblasts ``and production of `` `` collagen, `` `` fibronectin, and `` `` proteoglycans `` TGF-β is involved in the development of `` fibrosis in a variety of `` `` chronic inflammatory conditions `` `` `` particularly in the `` `` `` `` lungs, `` `` `` `` kidney, and `` `` ` `` liver `` TGF-β has a strong anti-inflammatory effect |
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Wound Healing
Growth factors Transforming Growth Factor β (TGF-β) |
has multiple and often opposing effects
`` depending on `` `` the tissue and `` `` the type of injury: growth inhibitor for most `` `` epithelia and `` `` leukocytes; generally stimulates `` `` proliferation and `` `` chemotaxis `` of fibroblasts ``and production of `` `` collagen, `` `` fibronectin, and `` `` proteoglycans TGF-β is involved in the development of `` fibrosis in a variety of `` `` chronic inflammatory conditions `` `` `` particularly in the `` `` `` `` lungs, `` `` `` `` kidney, and `` `` ` `` liver TGF-β has a strong anti-inflammatory effect |
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GENERAL FEATURES OF THE IMMUNE SYSTEM
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Function of the immune system is to protect animals from pathogens.
The mechanisms that are responsible for this protection fall into two broad categories: innate immunity (also called constitutive or native immunity) adaptive immunity (also called acquired or specific immunity |
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Innate immunity
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Innate immunity refers to
`` defense mechanisms that are present even before infection `` `` (without requirements of previous exposure to pathogen/antigen) Have evolved to specifically `` recognize microbes `` and protect multicellular organisms against infections |
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The major components of innate immunity are:
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1. Barriers
2. Acute phase response 3. Humoral innate immunity 4. Cellular innate immunity |
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Innate Immunity
Barriers 3 |
Physical barriers
`` Static barriers: `` `` epithelial surfaces prevent pathogen invasion `` Kinetic barriers: `` `` `` mucociliary clearance of respiratory tract `` `` `` peristalsis in gastrointestinal tract `` removes pathogens form the host surfaces Biological barriers: `` normal microflora of `` `` gastrointestinal, `` `` upper-respiratory and `` `` dermal surfaces `` competitively inhibits `` `` colonization and `` `` invasion `` by pathogens Chemical: `` gastric hydrochloric acid `` `` kills many ingested pathogens |
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Innate Immunity
Acute phase response 3 |
Acute phase proteins
Systemic reactions: `` fever, `` chills `` `` (search for warmth), `` anorexia `` somnolence Systemic hypoferremia ``to withhold iron from invading pathogens |
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Innate Immunity
Humoral innate immunity 4 |
Microbicidal components:
`` MAC of complement `` Defensins and lysozyme `` `` secreted on `` `` `` mucosal and `` `` `` dermal surfaces Microbiostatic components `` Metal binding proteins `` `` transferrin, `` `` lactoferrin Opsonins `` Lectins: `` `` mannose binding lectin, `` `` C-reactive protein, `` `` surfactant(-like) proteins Acute phase proteins |
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Innate Immunity
Cellular innate immunity |
Phagocytes
`` macrophages and `` neutrophils Natural killer (NK) cells |
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Adaptive immunity
Adaptive immunity consists of |
mechanisms that are stimulated by (adapted to)
`` previous exposure to microbes `` and are capable of also `` `` recognizing non-microbial substances, `` `` called antigens. Innate immunity is the first line of defense, because it `` is always ready to `` `` prevent and `` `` eradicate infections Adaptive immunity develops later after `` exposure to microbes and `` is even more powerful in combating infections |
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Adaptive immunity
There are two main types of adaptive immunity: |
cellular immunity
`` `` (mediated by T- lymphocytes), `` which is responsible for defense against `` `` intracellular microbes, humoral immunity `` `` (mediated by B lymphocytes and their secreted antibodies), `` which protects against `` `` extracellular microbes and their toxins. |
|
Adaptive immunity
Although vital to survival, the immune system is similar to |
the proverbial two-edged sword
On the one hand, `` immunodeficiency states render animal to be an `` `` easy prey to infections on the other hand, `` a hyperactive immune system may cause `` `` fatal disease |
|
Adaptive immunity
failure to distinguish self from non-self may result in |
immune reactions against animal’s own tissues
`` autoimmunity |
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Immunodeficiency disorders can be divided into
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primary immunodeficiency
`` (inherited) secondary immunodeficiency `` (acquired) |
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Primary immunodeficiencies
Primary immunodeficiencies are |
rare in animals
|
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Primary immunodeficiencies
Chediak-Higashi syndrome |
Hereford cattle, Persian cats etc
Defective killing of `` phagocytosed microorganisms `` due to abnormal lysosomes Abnormal pigmentation of melanocytes |
|
Primary immunodeficiencies
Leukocyte adhesion deficiency |
Irish setters and Holsteins
Persistent neutrophilia Defect in ß2 integrin, `` therefore circulating neutrophils `` `` cannot bind firmly to endothelium `` `` `` and exit blood vessels towards infection site |
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Primary immunodeficiencies
Severe combined immunodeficiency (SCID) |
Arabian foals, dogs and mice
Defects in both `` humoral and `` cell-mediated immune responses Affected Arabian foals are `` clinically normal from `` `` birth to 1-3 months `` when they are protected by `` `` passively transferred colostral maternal immunoglobulins `` The loss of passive immunity `` combined with the humoral and cellular immunodeficiency result in `` `` fatal respiratory and `` `` gastrointestinal infections `` `` `` adenovirus, `` `` `` Pneumocystis carinii, `` `` `` common bacteria Gross lesion: `` small or absent thymus `` and lesions associated with infections `` `` pneumonia |
|
Secondary immunodeficiencies
Acquired (secondary) immunodeficiencies are |
much more common in animals than primary immunodeficiencies
|
|
Secondary immunodeficiencies
Animal AIDS |
Simian immunodeficiency virus (SIV) in Old World monkeys
`` (e.g. rhesus – Macaca mulatta) Feline immunodeficiency virus (FIV) `` During the prolonged asymptomatic period, `` `` progressive loss of T-lymphocytes results in `` `` `` immunodeficiency with `` `` `` `` consequential chronic and recurrent opportunistic infections `` `` `` `` `` which are eventually fatal `` (Gingivitis is often the first sign of FIV infection `` Biting is the principal mode of `` `` FIV transmission, `` `` `` accordingly, highest incidence is in `` `` `` `` outdoor male cats |
|
Secondary immunodeficiencies
Lymphotropic viruses |
Bovine viral diarrhea virus is
`` `` epitheliotropic and `` `` lymphotropic `` Accordingly it causes `` `` erosions in the `` `` upper alimentary tract `` `` `` mouth, `` `` `` esophagus and `` `` `` rumen `` `` and in the `` `` `` interdigital areas `` `` as well as marked generalized lymphoid depletion `` `` `` necrosis of Peyers patches Canine parvovirus and feline panleukopenia (parvovirus) virus `` affect proliferating cells; `` accordingly, it destroys `` `` predominantly cryptal epithelial cells `` `` `` in small intestines causing `` `` `` `` enteritis and `` `` `` mild peritonitis `` `` and bone marrow cells `` `` `` causing panleukopenia and `` `` `` Peyers patches necrosis |
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Secondary immunodeficiencies
Failure of passive transfer of immunoglobulins |
This is the most common immunodeficiency disorder in domestic animals
Mammalian neonates are born with `` naïve acquired (specific) immune systems, `` `` such that they rely heavily on `` `` `` immune protection provided by their `` `` `` `` mother’s colostrum and milk This colostral immune protection is particularly important for `` neonates of species with `` `` epitheliochorial placentation, `` `` `` wherein the placenta is impermeable to `` `` `` `` large molecules such as immunoglobulins Accordingly, these neonates are born `` hypogammaglobulinemic and, `` `` therefore, must rely on colostral immunoglobulins, `` `` `` which are absorbed across their `` `` `` `` gastrointestinal tracts during the first `` `` 24-48 hours of life Failure to do so results in `` increased susceptibility to infections `` and majority of these neonates will `` die due to `` `` septicemia often accompanied by `` `` `` fibrinous/fibrinopurulent `` `` `` `` meningitis, `` `` `` `` polyarthritis and `` `` `` `` polyserositis |
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Secondary immunodeficiencies
Steroid induced immunodeficiency/immunosuppression |
immunosuppression
`` and increased susceptibility to `` `` infectious diseases `` can result from Chronic stress, adrenal cortical tumor prolonged steroid therapy |
|
Secondary immunodeficiencies
Other causes |
- Malnutrition
- Chemotherapy - Radiation therapy - Age |
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Four basic immune reactions -
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types I, II, III, and IV -
mediate the tissue damage in `` hypersensitivity and `` autoimmune diseases |
|
Hypersensitivity is
|
an exaggerated immunological reaction to a
`` normally harmless antigenic stimulus resulting in `` injury to the host Prior sensitization to a specific antigen is `` required |
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Hypersensitivity disorders tend to be
|
mediated by type
`` I and `` IV reactions |
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Autoimmune diseases develop
|
when
`` `` antibodies or `` `` T cells `` are reactive against `` `` self-antigens |
|
Autoimmune diseases tend to be
|
mediated by type
`` II or `` III reactions although more than one mechanism may be involved |
|
Autoimmune diseases
Type I reactions |
(immediate hypersensitivity)
Mediated by active substances `` `` (e.g. histamine) `` released or formed de novo by `` `` mast cells and `` `` basophils `` following reaction between `` `` antigen and `` `` specific antibody `` `` `` (usually IgE) `` bound to receptors on `` `` the membrane of the `` `` `` mast cells or `` ``` `` basophils Can be systemic and/or local Inherited predisposition exists Examples: `` atopic dermatitis, `` insect bite hypersensitivity, `` food allergy, `` drug eruption, `` anaphylaxis |
|
Autoimmune diseases
Type II reactions |
(cytotoxic hypersensitivity)
Cytotoxic reactions involving interaction of `` `` IgG or `` `` IgM `` with antigens bound on `` `` cellular membranes `` complement fixation frequently occurs, `` `` leading to cellular damage Cell damage is mediated by: `` Complement `` Antibody-dependent cell-mediated cytotoxicity `` Antibody-dependent cell dysfunction Examples: `` pemphigus, `` iso-immune thrombocytopenia, `` immune mediated hemolytic anemia, `` myasthenia gravis |
|
Autoimmune diseases
Type III reactions |
[immune-complex (Arthus) hypersensitivity]
Immune complexes `` `` IgG or IgM + antigen `` deposit in tissues `` `` and fix complement generating `` `` `` cytokines and other factors that `` `` `` `` attract neutrophils Examples: `` immune mediated glomerulonephritis, `` equine purpura hemorrhagica (S. equi), `` systemic lupus erythematosus, `` feline infectious peritonitis |
|
Autoimmune diseases
Type IV reactions |
(delayed hypersensitivity)
Mediated by `` sensitized T cells that, `` `` after contacting a specific antigen, `` `` `` release cytokines attracting `` `` `` `` macrophages and/or `` `` `` `` recruit other lymphocytes that are cytotoxic Examples: `` some drug eruptions, `` granulomatous diseases `` `` tuberculosis |
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Atopy
|
(atopic dermatitis, allergic inhalant dermatitis)
Type I hypersensitivity reaction Skin is the major target organ in `` dogs, `` cats, and `` horses Route of allergen exposure is `` suspected to be predominantly respiratory `` `` (at least in dogs) There is an inherited predisposition to `` develop immediate hypersensitivity reaction to `` `` a variety of antigens by `` `` `` excessive production of IgE `` which, when coupled to a `` `` specific antigen, trigger `` `` `` degranulation of `` `` `` `` dermal mast cells and `` `` `` `` circulating basophils Lesions: `` erythema, `` urticaria, `` self-inflicted trauma `` `` `` licking, `` `` `` rubbing `` `` due to pruritus |
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Erythema -
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redness due to capillary dilation
|
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Urticaria -
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eruption of itching wheals
`` acute dermal edema and `` erythema |
|
Food hypersensitivity dermatitis
|
Type
`` `` I and/or `` `` type IV `` reaction to food antigens Non-seasonal pruritic disease in young dogs Lesions: `` erythema, `` urticaria, `` self-inflicted trauma `` `` `` licking, `` `` `` rubbing ``` `` due to pruritus |
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Pemphigus
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Dermal disease caused by
`` type II reaction. Pathogenesis: `` Development of antidesmosomal auto-antibodies `` `` which bind to desmosomal proteins `` `` (interepithelial attachment proteins) `` and, subsequently, `` `` disruption of cell-cell adhesion, `` resulting in formation of intraepithelial pustules Lesions: `` intraepithelial pustules `` `` muzzle, `` `` periocular, `` `` pinnae, `` `` foot pads, `` `` around nails `` or erosions following pustular ruptures |
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Acquired Myasthenia Gravis
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Systemic muscular disease caused by
`` type II reaction `` `` mediated by antibody-dependent dysfunction Auto-antibodies are developed against `` acetylcholine receptors `` `` which are then masked by attached antibodies; `` therefore, receptors cannot `` `` interact with acetylcholine Clinical signs: `` muscle weakness and fatigue `` `` exacerbated by exercise `` and resolves with rest It is most commonly seen in `` adult dogs that might have megaesophagus `` `` +/- aspiration pneumonia |
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Iso-immune thrombocytopenia in piglets
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Sows are sensitized to
`` platelet antigens of `` `` fetal piglets `` and develop anti-platelet antibodies `` `` that are secreted into colostrum Ingested colostral antibodies are `` absorbed by piglets the antibodies bind to platelets `` and platelets are subsequently destroyed This results in `` thrombocytopenia `` and widespread hemorrhages |
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Neonatal isoerythrolysis in foals
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mare is sensitized to
`` erythrocytic antigens of a foal `` and develops anti-erythrocyte antibodies that `` `` are secreted into colostrum Ingested colostral antibodies are `` absorbed by a foal; the antibodies bind to `` erythrocytes, which are `` `` subsequently destroyed by `` `` `` complement `` `` `` `` (intravascular hemolysis) This may result in `` fatal anemia, `` icterus, `` hemoglobinemia and `` hemoglobinuria |
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Idiopathic immune-mediated haemolytic anemia
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most common in dogs.
Auto-antibodies are developed against `` erythrocytic antigens Erythrocytes coated by antibodies `` `` (IgG) `` are phagocytosed by macrophages `` `` predominantly in spleen `` `` `` (extravascular hemolysis) `` and sometimes lysed `` `` (hemolysis) `` by complement `` `` (intravascular hemolysis) `` with IgM The most common lesions: `` regenerative anemia, `` icterus, `` enlarged spleen `` `` due to `` `` `` activation ofmacrophages and `` `` `` extramedullary hematopoiesis `` bone marrow hyperplasia `` `` diffusely red |
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Equine purpura haemorrhagica
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After Streptococcus equi infection
`` `` (strngles) `` small percentage of horses have `` `` high level of antigen `` `` `` (protein M) `` `` antibody `` `` `` IgA and `` `` `` IgM `` complexes in circulation which are deposited in vessels `` tf `` `` consequential vasculitis, `` `` generalized edema and `` `` purpura |
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Feline infectious peritonitis
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It is a
`` `` progressive `` `` fatal `` immune-mediate disease of cats `` caused by a coronavirus FIP virus is spread systemically by `` infected macrophages Immune complexes `` `` (virus+Ab or viral antigen+Ab) `` are deposited on venular walls and cause `` `` type III immune reaction Based on experimental infections it seems that `` the ultimate outcome of FIP viral infection depends `` `` on cell mediated immunity `` `` `` (CMI) If CMI is strong and rapid `` virus will be contained `` `` (latent carrier) `` and subsequently eradicated If CMI is weak, `` effusive form of FIP will occur `` with marked fibrinous exudation in `` `` serosal cavities If CMI is moderately strong, `` dry form with `` `` granulomatous/pyogranulomatous infiltrate `` will occur in many organs `` `` kidney, `` `` liver, `` `` lung, `` `` eyes, `` `` meninges, `` `` etc |
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AMYLOIDOSIS
Amyloid is a |
pathologic proteinaceous substance,
`` deposited between cells in `` `` various tissues and organs of the body `` in a wide variety of `` `` clinical settings |
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AMYLOIDOSIS
Clinical diagnosis of amyloidosis ultimately depends on |
morphologic identification of
`` amyloid in biopsy specimens by `` `` light microscopy Amyloid is `` `` amorphous, `` `` eosinophilic, `` `` hyaline, `` `` extracellular `` `` substance that has `` characteristic histochemical properties `` `` Congo red stain, `` `` `` which under ordinary light imparts a `` `` `` `` pink or red color to tissue deposits, `` `` `` but far more dramatic and specific is `` `` `` `` the green birefringence of the stained amyloid `` `` `` `` `` when observed by polarizing microscopy |
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AMYLOIDOSIS
Despite the fact that all deposits have a uniform appearance |
(ß-pleated sheet fibrils)
`` and tinctorial characteristics, amyloid is not a chemically distinct entity |
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Amyloidosis
AA AL IAPP |
Serum amyloid A
`` Chronic inflammation Ig light chain `` Plasmacytoma Islet amyloid polypeptide `` Pancreatic islets |
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AA amyloidosis is
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most common systemic form in animals
It originates from `` serum amyloid A `` `` that is an acute phase protein in many species Concentration of SAA is increased during `` inflammatory diseases, `` even though its function is `` `` not known. |
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AL amyloidosisis
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rarely seen in animals
`` it is largely a disease of humans In dogs `` AL amyloidosis is associated with `` localized plasmacytomas |
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IAPP amyloidosis is
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relatively common in
`` old cats and `` non-human primates Pancreatic islet amyloidosis is associated with `` diabetes mellitus in `` cats Islet amyloid polypeptide (IAPP) is `` a normal component co-secreted with `` `` insulin by `` `` `` ß-cells However, if IAPPs change conformation `` and are deposited in `` `` islets, `` `` `` amyloidosis will occur |
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Renal amyloidosis
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Animals with progressive renal amyloidosis
`` die with `` `` renal failure and `` `` uremia Kidneys of these animals are `` enlarged and `` pale yellow-brown Amyloid may be accumulated in `` `` glomeruli, `` `` below basement membrane of renal tubules and `` `` in small arterioles Glomerular amyloidosis interferes with `` normal filtration `` and results in `` `` proteinuria Ultimately, amyloid interferes with `` `` blood supply to the `` `` entire nephron and `` `` `` renal tubular atrophy with `` `` `` `` uremia `` `` `` occurs |