Terms in this set (470)
What is inflammation?
vascular and cellular response of living tissue to injury
main defense of body against all types of injury
What are the five cardinal signs (clinical signs) of inflammation?
loss of fxn
What are four causes of inflammation?
What are the two responses to inflammation?
What occurs first in the vascular response?
dilation of blood vessels
What does dilation of blood vessels cause in inflammation? Where does it occur first?
occurs immediately first in arterioles
causes bright red area (REDNESS) and also cause of HEAT
What causes the blood vessels to dilate in response to injury? What else does this cause?
chemical substances from mast cells, monocytes, injured cells and plasma factors
increased vascular permeability
What are the three mechanisms of extravasation (increased permeability)?
endothelial cell contractions widening gap jxns
direct injury to endothelial wall causing leakage
leukocyte induced injury during leukocyte adhesion cascade causing leakage
What widens with endothelial cell contractions causing increased permeability?
Vascular permeability is related more to the _____ of injury than to the _____ of the injury.
What vessels are more permeable in mild injury?
post capillary venules
What vessels are more permeable in moderate injury?
capillaries and small venules
What vessels are more permeable in very severe injury?
What is immediate transient response (monophasic)? What vessels is it in and what is it mediated by? (2)
vascular leakage that occurs rapidly and is short lived
only in post capillary venules
mediated by histamine and serotonin
What is immediate prolonged response (biphasic)? What vessels is it in and what is it mediated by? (early and late phase)
occurs in severe injury and involves capillaries and venules
mediated by kinin in early phase and prostaglandins, leukotrines in later phase
What is sustained/prolonged response (direct injury to endothelial cells)? What vessels is it in and what is it mediated by? (3)
severest injury, involves venules, capillaries and arterioles
mediated by histamine, kinin and prostaglandins
What causes the change in rate of blood flow slowing and sometimes stopping bloodflow? (3)
increased viscosity (due to loss of fluid)
stasis of lymph flow
What are the changes in the blood stream? (axial/plasmatic zones)
cells normally flow in central Axial Zone with cell free Plasmatic zone surrounding it but with slowing of blood cells start flowing in plasmatic zone as well
What occurs during margination, rolling and adhesion of leukocytes causing blood slowing?
margination is leukocytes flowing on periphery
then roll along endothelium and when they can rest at some point they adhere to vessel wall
What is adhesion primarily caused by?
binding of complementary adhesion molecules on leukocyte and endothelial cells like a lock and key
What happens with leukocytes following adhesion?
leukocytes insert pseudopodia into jxns between enothelial cells
What are four chemotactic agents involved in leukocyte adhesion/immigration?
soluble bacteria products
components of complement system
products of lipoxigenase pathway of arachidonic acid metabolism
What are animals with leukocyte adhesion deficiencies (LAD) (2) and what are they lacking? What does this cause?
In dogs (irish setters) and cattle - lack functional expression of beta 2 integrins resulting in impaired passage of neutrophils across vascular walls
What do cattle with BLAD develop? (6) When does death occur?
severe gingivitis, tooth loss, oral/enteric ulcers, cutaneous ulcers, abcsesses and pneumonia
die in days/weeks after birth
How is BLAD acquired in holstein cattle?
lethal inherited recessive trait
What is exudation? What is it caused by? (2)
inflammatory fluid formation due to increased osmotic pressure in tissue and increased hydrostatic pressure in capillaries
What are the four beneficial effects of exudate?
brings Ab's to area of inflammation
fibrin network helps leukocytes crawl
limits areas of inflammation
Where are chemical mediators from? (2)
some released from tissues and some are components of plasma
What is histamine? Serotonin?
histamine = granules of basophils, mast cells and blood platelets
serotonin= mast cell granules in rodents, argentaffin cells of intestine and platelets of mammals
What do histamine and serotonin cause?
early transient dilation of blood vessels
What do histamine, serotonin and bradykinin cause?
interceullular gaps by endothelial cell contraction causing increased permeability
What are kinins?
polypeptides in circulating blood that arise from globulin fraction, follows tissue damage
What are the three actions of kinin system?
What is the complement system?
self assembling protein present in inactive form in plasma and body fluids
What does the C3a, C5a complement cause? (2)
increased vascular permeability and chemotaxis
What does C5a cause in leukocytes? (3)
leukocyte adhesion, chemotaxis and activation
What does the C3b, C3bi cause?
opsonins for phagocytosis
What is another name for the clotting system?
What is intimately connected with the clotting system?
What is the fibrinolytic system important for?
dissolition of fibrin clot
How is fibrin dissolved? (3)
fibrinolytic enzymes released from living and dead leukoytes
direct removal by phagocytic leukoctyes (neutrophils)
plasmin degrades fibrin
What are the two functions of plasmin in inflammation?
degrades fibrin into fibrin split products
cleaves C3 of complement
Where are prostagalndin and leukotriens derived from?
metabolism of arachidonic acid
What do the following prostaglandins and leukotriens cause:
PGE2 and PGI2
Leuko C4, D4, E4
PG and leuko in general
PGE2 and PGI2 = vasodilation
PGE2 = hyperalgesia
LeukoB4 = powerful chemotactic agent
Leuko C4, D4, E4 = vascular permeability
PG and leuko = sm mm contraction
What do prostaglandins and leukotriens enhance the action of?
histamine and kinin
What are the two causes of pain in inflammation?
prostaglandins and exudate
What is heparin released from? What does it cause? Prolong?
from mast cells
causes anticoagulant effect on fibrin and prolongs process of exudation in inflammation
What does the chemical mediator nitric oxide cause? (2)
causes vasodilation by relaxing sm mm cells
regulates leukocyte chemotaxis
WHat are cytokines? What do they regulate?
hormone like polypeptides secreted by inflammatory cells
regulate cellular immune response
What does Interleukin I stimulate? What secretes it?
initial phase of inflammation
WHat secretes Interleukin 6? What is its function? (2)
stimulates initial inflammation
converts B cells into plasma cells
What is the main function of Interleukin 12?
stimulates Th1 cells (Thelper)
What secretes Interleukin 18? Function?
stimulates T helper cells
What is the function of TNF? (3)
stimulate initial inflammation
controls body mass - overproduction causes weight loss
necrosis of tumor cells by apoptosis
What are the two types of interferons?
1 = antiviral
2 = gamma, produced by Th-1, stimulated by IL12 and 18
What is the function of chemokines?
cytokines that act as chemotactic agent to attract luekocytes to inflammation
What are the three mediators of vasodilation?
What mediators increases vascular permeability in inflammation? (5)
PAF (platelet activating factor)
What mediators cause leukocyte activation and chemotaxis? (5)
WHat mediators cause fever? (4)
cytokines IL1, IL6, TNF
WHat causes tissue damage in inflammation? (3)
reactive oxygen species
What is another name for neutrophils?
polymorphnuclear leukocytes or pus cells
What are the three properties of neutrophils?
phagocytic and kill microorganisms and tumor cells
ability to digest particulate matter
What do neutrophils phagocytose?
small foreign material such as carbon, pigment, cell debris, bacteria, fungi, protozoa and viruses
both indigestible and digestible material
What do neutrophils help release from mast cells?
What are the two functions of neutrophils?
phagocytosis and release of histamine
What are the two mechanisms nuetrophils use to destroy phagocytosed material?
digestion by substances in leukoctye granules
What is respiratory burst?
oxygen dependent killing of bacterial/digestible material by a burst of oxygen consumption by leukocytes which oxidizes NADPH to reduce oxygen to superoxide
Is digestion by substances in leukocyte granules oxygen dependent? What are the types of granules used (4) and what degrades bacteria?
non oxygen dependent
granules include bacterial permeability increasing (BPI) protein, lactoferin, lysozymes and defensin
after killing acid hydrolases found in azurophil granules degrade bacteria
What are the three ways neutropenia occurs?
acute tissue demand (acute inflammation and sepsis)
decreased bone marrow production (toxic conditions and immune mediated response)
increased margination (anaphylaxis and endotoxemia)
What is the percent of neutrophils in carnivores vs. ruminants/lab animals vs. horse?
carnivores = 60-70%
rumi/lab animal = 20-30%
horse = 50%
What message do neutrophils send to bone marrow?
send Colony Stimulating factor saying send more neutrophils
What are the two types of left shift?
regenerative - both mature and immature neutrophils are increase
degenerative - immature increases but mature normal or decreased
What is physiologic neutrophilia?
caused by fear, excitement, exercise and seizures
epinephrine causes release
What causes corticosteroid or stress induced neutrophilia? (3)
pain, trauma, transport and other painful conditions
What causes neutrophilia of acute inflammation? (4) What type of neutrophil increases?
inflammation, sepsis, necrosis and immune
increase in segmented/band neutrophils
What causes neutrophilia of chronic inflammation? (4) What is seen in lab tests? (3)
chronic suppurative lesions: pyometra, pyothorax, pyoderma, neoplasms
left shift, monocytosis, hyperglobinemia
What are eosinophils?
large, amoeboid phagocytic blood cells (larger than neutrophils)
What do eosinophil nuclei look like in dogs/horses vs. other spp?
dogs/horses have bilobed
others have more than two
How long do eosinophils remain in circulation? Tissues?
30 min then move to tissues with half life of 12 days
What are the three fxns of eosinophils?
phagocytic (lesser extent than neutrophils)
cytotoxic to parasite (MAIN)
augment/modulate allergic rxns
When does blood eosinophilia occur? Tissue eosinophilia?
parasitic conditions mainly
migrating phase of parasites causes tissue esosinophilia
What type of eosinophilic granuloma do felines (3), canine, equines and all spp get?
feline- esosinophilic plaque, granuloma and ulcer
canine - eosinophilic granuloma in oral cavity
equine - collagenolytic granuloma
all spp - eosinophilic granuloma secondary to parasites
What type of eosinophilic myositis do dogs get?
masticatory myositis (atrophic myositis)
Where do basophils mature? What do their nuclei look like? How many are found in blood and what is the life span in tissues?
mature in bone marrow, have lobulated nucleus but small numbers are found in blood. Life span in tissues is several days
What do basophils release in inflammation? (3)
WHat do basophils lack?
WHen do large numbers of basopils infiltrate? (4)
inflammation of skin
Where are mast cells derived? What type of organs are they found in?
derived from bone marrow and found in organs rich in CT
Where are mast cells located?
at host-environmental junctions like skin, GIT and resp. tract
What is the mast cell life span in tissues?
In inflammation what do mast cells release? (3)
What do mast cells synthesize? (4)
What condition are mast cells important in?
WHat are the two groups of small lymphocytes that respond to specific antigens?
What are the mononuclear phagocytic cells? (4)
large mononuclear cells
What are the macrophage phagocytic system (MPS) cells? (6)
dendritic cells in skin and lymph glands
histiocytes in CT
monocytes of blood
mesangial cells in kidney
Where do the macrophages of tissure vs. the macrophages of CNS derive from?
tissue from monocytes in blood
CNS from microglia
What are the functions of macrophages? (4)
initiate CMI response by presenting antigens to lymphocytes
participate in regulation of iron stores
What are the three secretory functions of macrophages?
enzymes - lysosomes, protease, lipase
proinflammatory products - IL, TNF, PAF, Pg
Growth factors -help healing process
What is monoctytosis? What does it indicate? (2)
increased circulating monocytes
indicates infllammation or tissue necrosis
What are resting macrophages stimulated by and what do they become? How do they become activated macrophages?
resting stimulated by inflammation (IL1 and IL6) making inflammatory macrophages
Inflammatory macrophages further stimulated by Interferons and bacterial products to become activated
What is increased from inflammatory to activated macrophages? (7)
MHC Class II expression
What are epithelioid cells? What condition are they asociated with?
hypertrophied foamy vacuolated macrophages named because of resemblance to epithelial cells in skin
associated with chronic inflammation
What are giant cells? When are they seen
large cells formed by fusion of macrophages by integration of plasma membrane and cell which forms many nuclei
seen in inflammation
What are the two types of giant cells?
Langhans type = nuclei on periphery
Foreign body giant cell = nuclei clustered in center or distributed in cytoplasm
What is the function of giant cells?
phagocytose bigger particles that macrophages weren't able to handle
What is inflammation classified according to? (2)
nature of exudate
What are the three sub groups of time classification of inflammation?
acute - shorter time
chronic - exudation subsides and repaire begins
subacute - mononuclear cells present and development of young capillaries and fibroblasts
What two things does the nature of the exudate depend on in inflammation?
causative nature of irritant
What is the main difference between acute and chronic inflammation?
repair is seen in chronic
WHat is the main leukocyte seen in acute vs. chronic inflammation?
neutrophils in acute
marophages in chronic
What is seen in luekocytes in subacute inflammation?
mixture of neutrophils and macrophages but 70% of neutrophils are dead
What does serous inflammation involve?
serous cavities lined by surface mesothelium like lung, skin and mucous surfaces
What are the causes of serous inflammation in:
serous cavities - infection (bacteria or viral)
joint cavities - trauma
lungs - infections, poisons, toxins
skin - toxins, trauma, burns (TQ)
muscous membranes - infection (usually viral)
What is the best example of serous inflammation?
second degree burns
Where is serous exudate found? What does the exudate look like? What does it stain?
body cavities, alveoli of lung and blisters of skin
looks clear/cloudy/blood tinged with high protein content and neutrophils
stains homogenous pink
What are the four effects of serous inflammation?
causes pain and loss of fxn
What is the main feature of fibrinous inflammation?
Where does fibrinous inflammation occur?
serous and mucous membranes (cardiac surface)
What serous area does fibrinous inflammation not occur in?
What is the gross appearance of fibrinous inflammation? Microscopic?
loss of shining/smoothness of serous surfaces with fibrin exudate on surface
stains dirty pink with leukocytes
WHat is fibrin membrane, pseudomembrane, dipteritic membrane and fibrin cast when describing gross appearance of fibrinous inflammation?
fibrin membrane is thin covering
pseudomembrane is thick and paper like
diptheric membrane is attached to surface of tissue
fibrin cast is large amounts of fibrinous exudate in organs that take shape of organ
What are the effects of fibrin inflammation? (3) Long term?
regeneration of underlying tissue
long term fibrin undergoes organization
What is organization of fibrin?
fibrinoblasts dissolve fibrin and scar formation takes place
Where is catarrhal or mucus inflammation from? Where is it seen?
mucus is component so from cells instead of blood
seen in mm of digestive, resp and repro tracts
What are the six causes of catarrhal/mucus inflammation?
bacteria/virus of LOW virulence
inhalation of dust
inhalation of foreign protein
chronic irritation of mucous surfaces by parasites
What are examples of low virulence viruses that cause mucus inflammation?
feline viral rhinotracheitis
What are examples of mild chemicals causing mucus inflammation?
What is the early and late stage gross and microscopic appearance of catarrhal/mucus inflammation?
exudate is clear or cloudy and may be blood stained, later stages changes to gray/yellow mixed with fibrin
stains pale blue with H&E, mucus producing cells show hypertrophy and surface epithelium shows desquamation
Where does hemorrhagic inflammation occur?
organs of rich blood supply like lung and digestive tract
What are the two causes of hemorrhagic inflammation?
micro-organisms of high virulence (clostridia, pasteurella, anthrax, lepto)
acute poisoning by phenol, arsenic or phosphorous
What does hemorrhagic inflammation look like?
large number of erythrocytes in exudate making it red, inside lumen or attached to mm
accompanies lesions of necrosis
What does hemorrhagic inflammation need to be differentiated from?
What will occur if the cause of hemorrhagic inflammation is not removed quickly?
Where is purulent inflammation found? What are the two causes?
pyogenic bacteria or fungal infections
What does purulent inflammation look like?
consists of pus, varies in color, liquid or solid, has degenerating/dead neutrophils
What is the most effective defense of the body against bacteria and fungal infection?
What are the two effects of purulent inflammation?
toxemia/death if toxic substances absorbed
rupture of abscess: internal is fatal, external is beneficial, metastatic (into circulation) is dangerous
What bacteria is most likely to form suppurative encephalitis (abscesses in brain)?
What is chronic inflammation?
inflammation of prolonged duration where active inflammation, tissue damage and repair are proceeding at the same time
What is the main reason for chronic inflammation? Three other causees?
main due to acute inflammation passing to chronic stage
also due to intracellular agents, autoimmune dz, toxic endogenous/exogenous substances
What three things characterize chronic inflammation?
infiltration of mononuclear cells
attempt at repair
What is granulomatous inflammation?
a special type of chronic inflammation in any tissue of the body (looks like a tumor but isn't)
What are the causes of infectious (3) vs. non-infectious (2) granulomatous inflammation?
infectious (bacteria, fungi, parasites)
non infectious (sx sutures, metal/wood/silica/carbon pieces)
What is the gross and microscopic appearance of granulomatous inflammation?
grossly a lump resembling a tumor
microscopically see young fibroblasts and capillaries like granulation tissue
WHat is diffuse vs. nodular granulomatous inflammation?
diffuse (lepromatous) granuloma (Johne's dz)
nodular (tuberculoid) granuloma
What is the effective defense of granulomatous inflammation against? What is the outcome of most?
effective defense against agents that cant be dealt with in normal inflammatory pathway
most infectious granulomas are fatal
What does the center of granulomatous inflammation have?
causative agent of granuloma
inflammatory cells surround it
What is lymphocytic infilatration seen in? (4)
lungs - called perobronchial cuffing
What is the effect/significance of lymphocytic infiltration? What infections is it seen in? (2)
not clear but observed in some viral/parasitic infections
What is healing?
process of replacement of damaged or dead tissue
What is healing by regeneration?
healing by SAME kind of cells
What is healing by repair?
damaged cells replaced with connective tissue
What are the three regenerative cells in the body?
stable cells (parenchymal cells/mesenchymal derivs)
What does the healing work of fibroblasts in the CNS?
microglia do the healing work instead of fibroblasts
What are labile cells?
continuously dividing cells (in skin, mucous membrane and bone marrow/lymphoid especially)
What are stable cells?
quiescent cells (in organs)
regenerative power decreases with age
What are permanent cells?
non-dividing cells (neurons, cardiac and sk mm cells) never regenerate, only repair
What is lost when healing by connective tissue repair? Two examples?
loss of specialized fxn of tissue
renal failure in fibrous replacement of kidney
heart failure in myocardial infarct and fibrosis
What is primary healing/primary union/healing by first intention? (repair by CT)
healing of a clean wound where tissues are opposed (sx sutures)
minimal tissue loss
What is the sequence of healing by first intention? (6)
endothelial regneration (blood vessels)
What is the fxn of the inflammatory response in healin by first intention?
remove dead tissue
How long does the endothelial regeneration take in healing by first intention? Epithelial?
What is secondary union/healing by second intention? (repair by CT)
healing of tissue where edges cannot be opposed (ulceration, infarct, abscess)
What are the three layers of healing by second intention?
superficial layer of cell debris
layer of angioblasts arranged at right angle to lesion
deep layer of fibroblasts parallel to lesion
What are the hypothesis (3) of stimuli for cell division?
cytokines and wound hormones
pressure gradients (contact inhibition)
What are the systemic factors affecting the adequacy and quality of repair? (internal factors) (3)
physiologic condition of host
What is contact inhibition?
when cells touch each other growth is inhibited but in injury that contat ceases allowing growth/repair to occur
What Vitamin has an effect on wound healing?
What endocrine factor delays healing?
What are the four local factors affecting quality and adequacy of repair?
mobility of tissues (keep immobile)
site of injury
What is immunopathology?
study of lesions induced by or resulting from immune mechanisms
What is Type I hypersensitivity?
from exposure to an antigen in a PREVIOUSLY sensitized host
Whatis the immunologic mediator of Type I hypersensitivity?
What are the two phases of pathogenesis of Type I? How can Type I be transfered to a normal animal?
sensitization phase and effector phase
can be transferred by injecting serum from a sensitized animal into a normal animal
How long is the reaction time of Type I?
What happens during the second exposure in Type I?
cross linking of 2 or more IgE molecules on surface of mast cell causing it to release inflammatory mediators
What causes sytemic anaphylaxis in type I hypersensitivity? (4)
parenteral injection of vaccines
ingestion of food
How is anaphylactic shock treated?
IV injection of epinephrine to counteract bronchial constriction
What is milk allergy?
in cows (especially Jersey) and sometimes mares in delayed milking due to milk casein gaining access to circulation prodcuing a type I sensitivity
show urticaria or anaphylaxis
What are localized type I hypersensitivity rxns due to? Where do lesions most commonly occur?
inhaled antigens, food antigens and drugs
on eptithelial surfaces like skin and mucosa of GIT
What are the 5 localized Type I hypersensitivity rxns?
chronic allergic bronchitis in dogs
What is type II hypersensitivity mediated by?
Ab's directed towards Ag on cell surface or cell surface receptor - this Ag may be intrinsic or exogenous
What does the reaction result from in Type II? Cause?
binding of Ab's to cell surface Ag's or cell surface receptors
causes cellular or tissue damage or activates/blocks the activation of the cell
What are the two ways complement dependent reaction (CDR) (Type II) can react?
Ab reacts with Ag on surface of cell causing actiation of complement system and disruption of membrane activity
or opsonization occurs (cells become susceptible to phagocytosis)
WHat type of cells does CDR mainly involve?
blood cells (red, white and platelets)
What causes CDR in blood cells? (4)
hemolytic anemia of newborn
autoimmune hemolytic anemia/agranulocytosis/thrombocytosis
What does a transfusion rxn result in?
massive hemolysis of red blood cells
What animals in hemolytic anemia of newborn common in?
occasional in dogs, cats,pigs and calves
What Ab are produced in autoimmune hemolytic anemia? What animals is it seen in?
Ab's against own blood cells
in cat dog and horse
What animal is auto immune thrombocytopenia common in? Two clinical signs?
epistaxis and hemorrhage in dogs
What happens in drug rxns to cause CDR?
Ab's react with drug and are complexed to red cell Ag
What is Ab dependent cell mediated cytotoxicity (ADCC)? (Type II)
needs cooperation of leukocytes instead of fixation of complement
What is Ab mediated cellular dysfunction? (Type II)
Ab's directed against cell surface receptors impair or dysregulate function
What are 7 examples of Ab mediated cellular dysfunction?
autoimmune thyroiditis in dogs and chickens
antiadrenocotical and antitesticular Ab's causing lesions
coon hound paralysis
myasthenia gravis in dogs
eosinophilic granuloma complex
What does tissue damage from type III hypersensitivity result from?
reaction from Ag-Ab complex
How does the size of the immune complex in Type III determine tissue damage? What else affects amount of damage?
if Ab is more than Ag the complex is large and removed but if Ag is more than Ab the complex is small and remains soluble so circulates longer (MAIN)
overload of immune complexes and intrinsic dysfunction of macrophage phagocyte system
What are the two categories of immune complex mediated disease?
generalized if complexes formed in circulation
localized if formed in certain oprgan/tissue
What is the pathogenesis of systemic immune complex disease?
complex formation in circulation
deposition of complex in tissue
What are examples of endogenous antigen that canform immune complexes? (3)
What are localized immune complex rxns best examplified by? Examples? (4)
arthus rxn - seen in animals that have circulating Ab's specific for an Ag administered parenterally
uveitis, vasculitis, purpura hemorrhagica and allergic pneumonitis
What individuals do generalized types of immune complex diseases form in? Example?
not previously sensitized animal
What is Serum Sickness?
when large amounts of Ag like horse serum is injected causing development of Ab's about two weeks later and formation of complexes that deposit in vessels
What is glomerulonephritis? What is it due to in cats vs. dogs?
immune mediated due to deposition of immune complex in glomerular capillary wall
cats due to FLV
dogs due to pyometra, adenovirus, neoplasia, SLE and heart worm
WHat is systemic lupus erythomatosus?
common in dogs, less in cats and rare in large animals
combo of type II and III hypersensitivity causing lesions all over
What are the two immune mediated arthopathies in dogs?
What is idiopathic polyarthritis? Common in what animals?
common in German Shperds, Dobermans, Retrievers, Spaniels and Pointers, Toy Poodles, Yorkies, Chihuahuas
no bony changes but synovial fluids are sterile and inflammatory
What is periarteritis nodosa or narcotizing polyarteritis?
most common in pigs associated with erysipelas and strep infection
What animal gets immune mediated meningitis?
What is hypersensitivity pneumonitis?
deposition of immune comnplexes in alveoli
called Farmer's lung in man and atypical pneumonia in cattle
What is vasculitis?
common in dogs and horses with drug induced more common in dogs, complex formation due to drug sensitivity
What is purpura hemorrhagica?
sequel of resp infection with strep equi
causes complex formation
What is anterior uveitis in dogs, cats and horses due to? (localized complex formation)
dogs - recovery from infectious canine hepatitis
cats - IFP infection
horses - immune rxn with leptospira and onchocerca
What is type IV hypersensitivity (DTH)?
lack of dependence on Ab, instead caused by sensitized lymphocytes so cannot be transferred from one animal to another by transfusing serum (unique)
When is the maximum intensity of DTH seen?
delayed - 24-48 hrs
What type of infections cause DTH? (2)
viral infections causing cytotoxic T cell allergic contact hypersensitivity
What is a classic example in vet med of DTH? Three other examples?
positive tuberculin test
contact dermatitis, flea allergy dermatitis, sweet itch
What is contact dermatitis and what animals is it found in? Rare in?
develops after sensitization by metals, plants, drugs (haptens) which aren't immunogenic but can bind to form a new antigenic protein causing host to mount a CMI response and damage skin
in dogs and horses but rare in cats
What is the antigen in FAD?
flea salivary antigen
What iis sweet itch in horses?
DTH cause by mosuito bite lesions are on mane tail and belly see allopecia, pruritis and inflammation
What do allergic dermatitis and sweet itch start as and go on tto develop?
start as type I then develop type IV component
What does neoplasia mean?
What is neoplasm? (5 characteristics)
growth of cells which grow without control of normal laws of growth, have no orderly arrangement, serve no useful fxn, resemble cells from which it arose, has no clear etiology
What is a tumor?
any kind of swelling, but now used to describe neoplastic swelling
Are all swellings tumors?
no, and not all tumors exhibit swelling
What does cancer mean in latin and greek?
grossly infiltrating tumors apparenlty look like crabs
What does malignant imply? What abilities does a malignant tumor have? (2)
cancer = malignant tumor
abillity to invade locally and destroy plus ability to spread (metastasis)
What is oncology?
study of tumors
What are tumors classified based on?
histogenesis (tissue or cell type)
behavior (growth, infiltration, metastasis and clinical effects)
What is the suffix of benign vs. malignant tumors?
benign = oma
malignant = carcinoma for epithelial and sarcoma for mesenchymal tissue
WHat is a benign vs. malignant fibrous tumor?
What is a benign vs. malignant adipose tissue tumor?
What is a benign vs. malignant bone tumor?
What is a benign vs. malignant blood vessel tumor?
What is a benign vs.malignant mm tumor?
What is a benign vs. malignant glandular epithelium tumor?
Whatis a benign vs. malignant surface protective epithelium tumor?
What is a benign vs. malignant mammary gland tumor?
What is a benign vs. malignant liver cell tumor?
liver cell adenoma
What is a squamous cell (skin or esopphagus) benign vs. malignant tumor?
What is a transitional cell (urinary bladder) benign vs. malignant tumor?
transitional cell carcinoma
What germ layer is a sweat gland carcinoma derived from?
What germ layer is an intestinal carcinoma or pancreatic carcinoma derived from?
What germ layer is a renal carcinoma derived from?
If tumor contains bone or cartilage in addition to neoplastic epithelial cells what is that the result of?
metaplasia of myoepithelial cells and are not neoplastic cells
What do teratomas and teratocarcinomas arise from? Are they mixed tumors?
totipotential germs cells
contain tissue from all embryonic cell layers and have mix of adult and embryonic tissue types
neoplastic tissue is foreing to tissue inwhich it arises, but not mixed tumors
What is anaplasia?
when tumor cells don't resemble the parent tissue
What can degree of differentiation of tumors (well differentiated to very anaplastic) indicate?
degree of malignancy
WHat are examples of mixed tumors? (2)
mixed mammary gland tumor
mixed salivary gland tumor
What are benign and malignant melanocyte tumors?
What are malignant lymphocyte tumors?
lymphoma and lymphosarcoma
What are benign and malignant mast cell tumors?
mast cell tumor
mast cell sarcoma/mastocytoma
What are benign and malignant astroglia tumors?
astrocytoma for both
What are malignatn bone marrow tumors?
What is a neuroma?
disorganized mass growingfrom nerve tissue usually after trauma or amputation (docking in dogs)
What is a Hamartoma? What tissues are they normally in? (3)
hyperplastic mass of mature tissue as a result of anomalous development normal to location they are found
NOT a tumor but resembles a tumor
usually seen in ovar, lung and skin
WHat is a chriotoma? Example?
non neoloplastic normal mature tissue that does not normally occur in that site
example = dermoid
What is the difference between benign and malignant tumors in differentiation, loss of polarity, pleomorphism and nuclei?
differentiation of benign is good, variable in malignant
benign doesn't lose polarity, malignant does
benign doesn't have cell pleomorphism or nuclei changes and malignant has extreme changes
What is the difference in growth rate between benign and malignant tumors?
benign is slow with a few exceptions and malignantis often rapid
What is the growth type of benign and malignant tumors?
benign is expansion (space occupying lesion)
malignant is infiltration or invasion
What is the metastasis of benign vs. malignant tumors?
common in malignant but never occurs in benign
What are the clinical effects of both benign and malignant tumors?
What type of differentiation in tumors tends to grow more rapidly? What are the exceptions?
poorly differntiated ones except papillomas in dog mouths and hormone dependent mammary tumors in the bitch
What are the four most important criteria of benign tumors?
rarely invades surroundings
What are the two most important criteria of malignant tumors?
What is metastasis? AKA?
spread and growth of tumor in distant organ away from original site
aka secondary tumor
What are the five stages in metastatic processes?
invasion of lymphatic and/or blood vessels
invasion and growth
WHat five ways can a tumor metastasize?
blood vascular system (mesenchymal tumors)
lymphatic system (epithelial tumors)
along duct system
How do tumors metastasize through body cavities? What are examples? (3)
invasion through serous membranes and then implantation
splenic hemangiosarcoma, ovarian/intestinal/gastric carcinomas, pulmonary tumors
What are two examples of a tumors that spread along epithelium?
mammary carcinoma to skin of inguinal region
gastric carcinoma to esophagus
What are three examples of tumors that spread along duct system?
mammary gland tumors
renal pelvic tumors
What is an example of a self limiting tumor?
What are intermediate tumors? Examples? (3)
malignant but don't metastasize- have local invasiveness and cause death
basal cell carcinoma, sweat gland and sebaceous gland tumors
Is size an indication of prognosis in tumors?
What types of tumors are firm vs. soft?
scirrhous are firm
necrotic are soft
What does the color of most tumors resemble?
What can happen if a tumor diffusely infiltrates an organ? (example = splenic lymphosarcoma)
cause enlargement of organ
What can the microscopic appearance of tumors look like? (5)
sheet of cells
nest of cells
What is the microscopic appearance of a papilloma?
trabecular arrangement (crab like growth)
What is the difference between parenchyma and stroma of tumors?
parenchyma is the neoplastic cells
stroma is the supporting tissues that are host derived (non-neoplastic) and critical for tumor growth
What is angiogenesis?
development of new blood vessels in tumor
How big can a tumor get without angiogeneisis? What else is angiogenesisi required for?
required for metastasis
How do tumor cells stimulate angiogenesis? (2) What does hypoxia do to angiogenic factors? What do glucocorticoids do to angiogenesis?
secrete angio and anti-angiogenic factors
induce angiogenic factor secretion from other cells
hypoxia causes release of angiogenic factors
glucocorticoids interfere with angiogenesis
What do the endothelial cells of tumor blood vessels do?(2)
supply O2 and nutrients to tumor cells
secrete growth factors
What is the difference between tumor blood vessels and normal blood vessels?
tumor are more dilated, tortuous and permeable than normal
What does the vessel leakiness of tumor blood vessels allow for?
perivascular deposition of fibrin network that promotes formation of collagenous tumor stroma
Where do the growth factors that stimulate growth of tumor cells come from?
tumor blood vessels
What is required for metastasis of tumors?
adequate blood supply (tumor blood vessels)
What shares features of tumor angiogenesis?
What is the fibrous capsule common in benign tumors?
What can provoke fibroplasia? What does it need to be differentiated from? (3)
tumor cells provoke
differentiate from fibromas, fibrosarcomas, and other CT tumors
What is the nonspecific host response against tumors? Is it effective?
inflammatory response with lysis and phagocytosis
doesn't appear to be effective
What is the specific host response against tumors?
tumor antigens expressed on surface of neoplastic cells evoke anti-tumor Ab's and anti-tumor CTL's
What is the first line of defense against tumor cells?
innate immune system = macrophages and NK cells
How can NK cells kill tumor cells?
after binding tumor cell NK releases lytic granules that activate apoptosis in target cell
How can macrophages kill tumor cells? What are they independent of? Require?
by releasing reactive oxygen spp, nitric oxide, lysozymes and TNF
independent of MHC antigen but direct contact between macrophage and cell is required
What are most CTLs in adaptive antitumor effective response? What have they been primed by?
CD8 T lymphocytes that have been primed by dendritic cells to recognize and engage tumor antigens on the surface of tumor cells
What does the CTL release when in attaches to the target cell on the tumor and forms cell to cell contact?
lytic granules containing perforin and granzymes
What do perforin and granzymes released from the CTL do?
perforin mediates entry of granzymes into cell which initiates apoptosis
What do CD4 lymphocytes do in adaptive antitumor effective response?
helper cells to enhance CD8 function
How do B lymphocytes work against tumors?
antibody producing which kill tumorcells by generating membrane attack complex and ADCC
What is immunosurveillance?
immune system recognizing self antigens on tumor cells as foreign and attacking the cells
What happens if immunosurveillance fails?
allows tumors to emerge
If lymphocytes and macrophages are present within and around tumors what does that suggest?
the tumor can illicit an immune response
How can tumors evade the immune system? (6)
lack surface molecules that differentiate it from self
lose/mask tumor antigens
prolonged exposure induces tolerance
loss of MHC
bind/deplete anti-tumor Ab
cause T lymphocyte apoptosis
How can a tumor hide it's antigens?
when cells are complexed with glycocalyx molecules, fibrin or Ab's
What type of genetic damage is cancer associated with?
non-lethal genetic damage
What are the primary targets of genetic damage in cancer? (3)
genes that code for proteins that promote cell growth, inhibit cell growth, or regulate apoptosis
What are the proteins that promote cell gwoth called? What four things do these proteins regulate?
growth factors, growth factor receptors, signaling molecules, cell cycle regulators
Where are oncogenes derived from?
protooncogenes whose expression is deregulated
What happens when prootoncogenes are deregulated forming oncogenes? (3)
change in function
no longer regulated
What genes inhibit cell growth?
cancer suppressor genes
What do cancer suppressor genes encode?
nucelar proteins that suppress cell proliferation by preventing the entry of cells into growth cycle
What happens when cancer suppressor genes are lost or inactivated?
growth restraints are released and malignant transformation occurs
What does loss of function of proteins regulating apoptosis cause?
increased cell life span with increased opportunity to acquire mutation
What are known risk factors of acquiring cancer? (5)
What personal practices are known risk factors of cnacer? (4)
chronic irritation like smoking and tobacco, walking barefoot, sun exposure
Which diseases are known risk factors for cancer? (3)
Is cancer contagious?
not unless papillomavirus infection develops like in TVT in dogs or DFTD in tasmanian devils
Is cancer hereditary?
no, but tendency to develop it may be inherited
What swine canccer and dog cancer are more likley to by hereditary?
lymphoma in swine
osteosarcoma and melanoma in dog
What human cancer conditions are more likely to be herediatry? (3)
chronic ulcerative colitis
What age is papilloma more likely to occur?
What age is oral papillomatosis more likely to occur?
What age is perianal gland tumors more likely to occur?
What age is melanona more likely to occur?
older dogs and horses
What age is teratoma more likely to occur?
What age is fibrosarcoma and histocytoma more likely to occur?
What age is mammary tumor more likely to occur?
middle aged bitches
What are three known causes of cancer?
What do chemical carcinogens reactive electrophiles react with? (3)
What are the two different categories of reactive electrophiles?
directly acting = weak (some cancer drugs)
indirectly acting = most common, require enzymatic conversion in cell
WHat are three examples of chemical carcingogens?
polycyclic hydrocarbons (cigarettes)
What are chemical carcinogen examples in bovine? (2)
ingestion of bracken fern
bovine bladder tumors
WHat is a chemical carcinogen in cats?
feline vaccine associated sarcoma
WHat physical agent can be carcinogenic? (2) Examples of both?
radiation (x-ray and solar)
physical trauma (chronic irritation)
What can solar radiation cause in cattle?
squamous cell carcinoma in eye lid
What is the progression of squamous cell carcinoma in cattle?
begins as solar dermatosis then get ulceration and conjunctivits
Is squamous cell carcinoma slow or fast growing?
slow to metastasize
What is squamous cell carcinoma one of the main reasons for at slaughter?
WHat other animal is prone to squamous cell carcinoma?
WHat pollution associated squamous cell carcinomas exists in small animals? (4)
tonsil of dog
tongue of cat
esophagus of cat
nasal cavity of dog
What three animals get UV light associated skin tumors in the eyelid and cornea?
What animal gets UV light associated skin tumors on the vulva?
What two animals get UV light associated skin tumors on the muzzle?
WHat two animals get UV light associated skin tumors on the ear?
cat and sheep
What animal gets UV light associated skin tumors on the ventral abdomen?
WHat aree UV llight associated tummors normmall inn animalss? ((3) Humans? (2)
squamous cell carcinoma most common, could also be hemangioma and hemagiosarcoma
melanoma and basal cell carcinoma in humanss
What are the three viral carcinogens?
What animals do retroviruses affect? (3)
WHat are examples of viral oncogenes that acutely transform retroviruses? (2)
What are examples of slowly transforming retroviruses that activate other genes? (3)
What two RNA virueses have the cat as the natural host? What are two other eperimental hosts?
experimental in dog and rabbit
WHen the bovine papillomavirus infects horses what can it cause?
What do a small number of papillomaviruses progress into?
malignant transformation in bovine, canine and human
What are three bacteria associated with tumors? What do they cause?
H. pylori (humans)
H. mustelae (gastric carcinoma in ferrets)
Helicobacter spp (dogs/cats)
What is an esophogeal nematode of dogs and what does it cause?
causes granulomas leading to dyshagia and rarely esophogeal fibrosarcoma or osteosarcoma
What is the main theory of carcinogeneisis? (primary change and what this causes)
primary change is in DNA of cell because all known carcinogens act on DNA
this results in non-lethal genetic damage (somatic mutation) in a gene controlling cell division
WHat are four consequences of neoplasia?
WHat is a clinical sign of compression due to tumors?
What are clinical signs of obstruction due to tumors?
What are clinical signs of tissue damage due to tumors?
What are clinical signs of organ/tissue replacement due to tumors?
functional defects or death
What three active product might tumors produce that act systemically?
What tumor can produce insulin causing hypoglycemia?
What tumor can produice cortisol that causes cushings?
What tumor produces adrenalin causing hypertension?
What tumor produces estrogen causing feminiazation?
sertoli cell tumor
What tumor produces PTH like peptides causing hypercalcemia?
adenoma of anal sac in dogs
What tumor produces osteoclast activating factor causing hypercalcemia?
What tumor produces histamin causing gastric ulcers?
mast cell tumors
What is cancer cachexia? What is the mechanism?
loss of body fat and lean body mass due to TNFalpha and IL1/6 from macrophages suppressing appetite and inhibiting lipoprotein lipase
LMF increases catabolims and PIF decreases protein synthesis
How is fever caused by neoplasia?
cytokines cause local synthesis of prostaglandins in hypothalamus disturbing its function
How does neoplaasia cause anemia?
Il1 causes defect in iron transport and reutilization
How does neoplasia cause immmunosuppression?
TNF beta regulates immune reactions
What is the third most ccommmon teesticullar tuumor in dogs? What do 1/3 of these ttumors produce?
sertoli cell tumorss, usually in cryptorchid
1/33 produce estrogen causing feminization
What are paraneoplastic conditions? Common examplkes in vet med?
systemic complications of neoplasia that are removed from the primary tumor
due to production of native hormone either endogenously or ectopically
What two things can paraneoplastic conditions help with in vet med?
tumor markers for treatment and response
What are two examples of a paraneoplastic syndrome affecting metabolsim?
hypercalcemia due to secretion of PTH like proteins or osteoclasts activating factors
insulinoma causing hypoglycemia
What are clinical signs of paraneoplastic hypercalcemia? (7)
ischemic rnal injury
When will serum calcium levels retunr to normal in paraneoplastic hypercalcemia?
after surgical removal of tumor
What are the three most commonly associated tumors with hypercalcemia in dogs? (TQ) Cats?
anal sac adenocarcinoma
none in cats
What are the five tumors occasionally associated with hypercalcemia in dogs?
adenocarcinoma of mammary gland
squamous cell carcinoma
What are the three tumors occasionaly associated with hypercalcemia in cats?
squamous cell carcinoma
What tumor causes hypoglycemia in dogs and rarely in cats? Clinical signs? (4)
causes CNS dysfunction (lethargy, ataxia, polydipsia, seizures, and weakness)
Will removal of the insulinoma return sugar levels to normal?
What does hypertrophic (pulmonary) osteopathy affect? Where are the malignant tumors and non malignant disease?
syndrome affecting bones causing hyperplasia of surface of bone
a variety of malignant tumors in lungs of dogs and non-malignant diseases of the thorax
What other tumors besides hypertrophic osteopathy affect bones in dogs? (4)
rhabdomyosarcoma of urinary bladder
adenocarcinoma of esophageal glands and liver
What two tumors affect the bones in cats?
renal papillary adenosarcoma
What is the clinical sign of tumors affecting bones? Why?
sudden onset of lameness in all limbs as a result of periosteal proliferation in distal extremities
What tumors cause immunoglobulin production in dogs and cats? (2)
plasmacytoma and myeloma
What tumors cause thrombocytopenia by altering coagulability in dogs and cats, and just dogs (2)?
lymphoproliferative tumors in dogs/cats
sertoli cell tumor and DIC in hemangiosarcoma in dogs
What two tumors cause eosinophillia in cats?
MCT and lymphosarcoma in cats
What are definitive diagnoses of tumors based on? (2) What percentage can be diagnosed based on cytology?
histopathological and cytological exams of biopsies and aspirates
80%, only ones that can't are anaplastic
What are cells evaluted for in biopsies and aspirates to determine malignancy? (5)
high mitotic index
What does grading a tumor do?
gives indication of how similar the neoplastic cells are to normal cell counter parts (degree of differentiation)
What are the three tumor grades?
well differentiated = low grade - grade 1, cells are similar to normal cells
modeerately differentiated = medium grade - grade 2, somewhat similar to normal cells
Poorly differentiated = high grade 3, anaplastic cells
What are additional criteria for grading tumor cells besides differentiation? (4)
degree of necrosis
How does grading a tumor help in prognosis or response to therapy?
indication on biological behavior
What does staging a tumor do? What system is used?
gives indication of tumor growth and spread to help guide clinician on therapy and prognosis
TNM system is used = T is size of primary tumor, N is degree of lymph node involvement and M is extent of metastasis
What is the scale of the TNM system?
T1-T4 indicates increasing size of primary tumor
N0 is no involvement of LN and N1-N3 progressive
M0 is no metastasis M1 is metastasis to one organ M2 to two organs
WHat are the two disturbances of growth of cells?
failure of normal development
cellular adaptation to change
What are examples of failure of normal development? (3)
What is cellular adaptation to change?
compensatory or protective in response to demands for increased or decreased function
can be physiologic or pathologic
What are six cellular adaptations to change?
What is a physiological cellular adaptation to change?
involution of thymus in response to aging
What is aplasia?
organ did not develop during embryogenesis and is absent or rudimentary
What are examples of agenesis? (3)
one kidney, testes/ovary, tail/limb
What are the three forms of agenesis?
segmental aplasia (part of structure is absent)
What is the best example of segmental aplasia?
WHat is atresia?
absence or closure of opening, usually of a hollow visceral organ or duct (intestine, bile duct)
What is atresia ani? Atresia coli?
What is hypoplasia?
failure of organ to obtain full size which decreases function
When is hypoplasia normally noticed? What causes hypoplasia? (2)
due to events late in developing fetus/neonate because of viral infections of mother or genetics
What can feline panleukopenia cause hypoplasia in?
WHat causes cerebellar hypoplasia in calves and lambs?
BVD infection of cow
Blue Tongue Virus of ewe
What causes enamel hypoplasia in dogs?
canine distemper virus infection
Genetic hypoplasia is not completely understood but familial occurence occurs, what is seen in dogs and dogs/calves?
familial renal hypoplasia in dogs
pancreatic hypoplasia in calves and dogs
How can you tell the difference between aplasia with a rudimentary structure present and hypoplasia?
rudimentary structure lacks normal organ structure
hypoplasia shows recognizable normal architecture (with some abnormalities)
What is physiologic cellular adaptation to change a response to?
normal stimuli like hormones (lactation and mammary gland enlargement)
What is atrophy? What is it due to?
decrease in tissue mass AFTER acheiving normal growth
due to decreased cell number and/or decreased cell size
What are physiologic causes of atrophy? (3)
mammary gland involution
What are causes of pathologic atropy? (6)
WHat is disuse atrophy?
mm most affected tissue in severe lameness or cast/splint of limb
What is neurogenic atrophy? Example in horses?
loss of innervation of mm
roaring caused by atrophy of cricoarytenoid mm in larynx
What is vasculogenic atrophy?
loss of blood supply, mostly affects mm
What is nutritional atrophy? When is it seen? 2)
seen in old age and starvation (malnutrition, parasites, malabsorption and neoplasia cause starvation)
What are three examples of endocrine arophy?
involution of uterus after overioctomy
atrophy of zona fasciculata in hypercortisolism
hyperparathyroidism affecting bones
What are two examples of inflammatory atrophy in swine and dogs?
atrophic rhinits in swine
intestinal villii atrophy in parvo virus in dog
What animals is testicular atrophy mostly seen in? What are causes (6)
dogs and bull
WHat breeds of dog is pancreatic atrophy genetically inherited as autosomal recessive trait in?
rough coated collies
In other animals what is pancreatic atrophy due to? (5)
closure of pancreatic duct
What is autophagocytosis?
uptake and intracellular degradation of damaged organelles in cells with sublethal injuries
What is the mechanism of autophagocytosis?
damaged organelles are enveloped by cell membrane to form autophagosomes which fuse with lysosomes
What is autophagy common in? (2)
sublethally injured cells undergoing physiologic regression
What does autophagocytosis cause a decrease in the cell?
What is hypertrophy?
increased tissue size due to increase in cellular size
Where is the pure form of hypertrophy only seen?
in tissues composed of cells that do not readily divide like striated mm
What can accompany hypertrophy?
hyperplasia (increase in number of cells)
What are examples of physiologic hypertrophy? (3)
hypertrophy of uterus during pregnancy
mm hypertrophy due to weight lifting
cardiac hypertrophy due to athletic animal
What is an example of pathologic hypertrophy?
cardiac enlargement due to hypertension or aortic valve disease
How can an increased work load cause hypertrophy? (2)
increased demand of striated mm
renal hypertrophy after removal of one kidney (compensatory hypertrophy)
What organ will hyperparathyroidism cause hypertrophy in?
What organ will corticosteroids cause hypertrophy in?
What will androgens cause hypertrophy in?
What will estrogens cause hypertrophy in?
Is hyperplasia or hypertrophy more common?
What does hyperplasia do to function of an organ? Is the change reversible?
What are the two physiologic causes of hyperplasia?
hormonal (gravid uterus, lactation)
compensatory (remaining tissue enlarges after removal of part)
What can pathologic hyperplasia provide an initial change for?
future cancerous proliferation, but still controlled and reversible
What are three causes of pathologic hyperplasia?
What can cause both hypertrophy and hyperplasia?
What can chronic irritation be due to in pathologic hyperplasia? (2)
infectious or non infectious
What can chronic irritation caused by UTI or uroliths lead to?
What is metaplasia?? Is it reversible?
transformation of one adult cell type to another adult cell type of the same germ layer
Why does metaplasia occur?
germinal or stem cells undergo modified proliferations, NOT due to alterations in existing mature cells
Where does metaplasia usually occur?? (2)
What do columnar or cuboidal epithelial cells change to in metaplasia?
stratified squamous cells
What does CT change to in metaplasia? Cartilage?
CT to cartilage
cartilage to bone
What cause of metaplasia is seen in the lungs of smokers??
Where will a vitamin A deficiency cause metaplasia? (2)
epithelial cells in urinary tract/bladder
ducts of salivary/esophageal glands
Where will estrogen toxicity cause metaplasia??
squamous metaplasia in prostate and urinary tract
Where will blockage of ducts cause metaplasia?
biliary and pancreatic in presence of stones
What metaplasia is seen in bone marrow insufficiency?
What tumors is metaplasia seen in?
mixed mammary tumors
What is dysplasia?
abnormal development, mostly used to describe developmental defects
What are common examples of dysplasia? (2)
fibrous dysplasia of bone
What is dystrophy?
variety of progressive degenerating and atrophic changes resulting from defective nutrition (some are inherited)
What are three examples of dystrophy reported in animals??
osteodystrophies like ricketts and osteomalacia
mm dystrophies (inherited)
neuroaxonal dystrophies usually in sheep and dogs