■ Introduction ■ Pathology - the work of pathologist/physicians whose focus is on the physical

changes present in diseased organs and tissues.■ Pathophysiology - the abnormal functioning of diseased organs with application

to patient care. (physiology gone bad)■ Etiology - the study of the cause of a disease■ Idiopathic - etiology is unknown■ Three kinds of etiology:

1. Genetic etiology○ Genes are responsible for some structural or functional defects.

2. Congenital etiology○ Environmental issues effect prenatal development○ Ex. Cystic fibrosis

3. Acquired disease○ Encountered later in life, developed over time○ Tuberculosis, emphysema, hepatitis

■ Symptoms - reflect the patients subjective experiences, what the doc looks at■ Signs - are detected by the patient, rash or increased body temp■ Syndrome - combination of signs and symptoms■ Sequala - a condition resulting from a disease■ Acute - short, rapid growth■ Chronic - long duration■ Insidious - minor changes that don’t arouse immediate concern■ Local - one region of the body■ Focal - limited to one or more distinct sites■ Diffuse - is uniformly distributed■■ Diagnosis - the identification of the patients specific disease■ Prognosis - the prediction of a particular disease’s outcome■

■Chapter 1

■ At the subcellular level organelles perform various tasks for the overall function

■ The specialized functions are because of the chemical level. Atoms and molecules have random patterns of organization. Cells counter this, showing the distinctive difference of living vs non-living.

The Plasma Membrane

■ Cell/plasma membrane is made up of phospholipid, cholesterol, glycolipid, protein, and glycoprotein.

1. It defines the size and shape of cells and acts as a container.2. Selectively permeable – able to pass molecules between cells and environment;

like water. The movement of nutrients and waste. This is done through active transport expending energy.

○ Transporting ions through ion pumps○ Endocytosis - inward movement○ Exocytosis - outward movement

3. Provides the surface were the cell interacts with its environment. This can affect the permeability or cellular metabolism. Due to receptors forming carbohydrate component of glycoprotein.

The Mitochondrion

■ Many molecules that enter the cell through its membrane serve as an energy source. Glucose is the main energy source. The mitochondria extracts it converting it into ATP, available for transfer to various other metabolic pathways. Produced during the Krebs cycle, chemical transformations producing CO2.

■ Requires oxygen (aerobic). The sites of energy metabolism lines their enzymes. The enzymes are organized in the crista, folds, organelles are rich in protein, enzymes, much cell activity is devoted to protein synthesis.

Granular Endoplasmic Reticulum

Protein synthesis occurs in the cytoplasm (the fluid of the cell, water, solutes, and organelles)

○ Endoplasmic reticulum (ER) – connected by cisternae with small masses called ribosomes (protein) stores with the GER

The Golgi Complex

■ Consists of stacks of cisternae, which store the proteins often with carbohydrate or lipid to form a fully functional product for secretion. To be able to secrete it is passed to vesicles (sacs) to be transported to the cell membrane

Agranular Endoplasmic Reticulum

1. it detoxifies, to chemically degrade hormones, drugs, or toxins2. For a formation of lipids, phospholipids, triglycerides, and steroids

The Lysosome

■ Digest enzymes that are not needed. Also known as a phagosome

The Cytoskeleton

■ Thin filaments that support and organize of organelles/cell structure

The Nucleus

■ The control of the cell. Contains chromosomes/DNA structure

Causes of cell injury

■ Three ways a cell can be injured:○ The lack of a substance necessary to the cell – a defiency○ The presence of a substance that interferes with cell function – poison or

intoxication○ The loss of the cell’s structural integrity – physical injury, trauma

Deficiency

■ Cells need a constant supply of chemical nutrients and energy. Heart attacks are of the most common because there is a lack of oxygen or nutrients. Lack of thiamin causes damage to nervous tissue.

■ Primary- there are none present■ Secondary- they are there, but cannot be absorbed

○ Genetics can cause precursors○ Viral action- infected, having a heavy demand for particles disrupting the

cell’s metabolism

Intoxication

■ Exogenous Toxins- are external, biological, or nonbiological○ Biological- are known as infections○ Nonbiological- chemicals outside the body either inhaled or swallowed

■■ Endogenous Toxins- within the body

○ Genetic- which causes toxin to be produced○ Impaired Circulation- when metabolic by-products accumulate. The injury

occurs by binding to the cell structure, disrupting function○

Trauma

■ Trauma is a physical injury. The integrity of the cell can be completely lost. ○ Extreme cold (hypothermia) disrupting cell proteins

○ Excessive heat- denatures cells, disforming helix○ Burns, suns radiation can be gradual

■ Ionizing radiation- through x-rays/nuclear radioactivity. Produces free radicals. ○ Strips electrons from cell molecules○ Mechanical pressure, tumor or expanding arteries

■ Physical injury- bacteria from potent enzymes/viral infections■ Immune system- when attempting to protect us it could end up hurting us.

Antigen- antibody at cell surfaces cause disruption on cell membrane. One virus can produce several other occurring viruses.

■ These viruses cause other cells to attack this now foreign cell which causes cell death/trauma

Cell Injury: Responses and Effects● Cells can activate various adaptive responses that can them cope with

certain situations● A cells damage is determined by the nature, intensity, duration, and number

of exposures to it● When a cell is restored from injury this is known as a reversible change.

Reversible Changes: Functional● Cells are very adaptive when necessary and once back to normal can then be

deactivated. ● Alternative Metabolism- in unfavorable conditions, a cell can employ

alternative metabolic pathways that allow it to adjust to the conditions○ This can be seen when oxygen dependent (aerobic) is threatened, so

tissues adapt to glycolysis, allowing ATP to be reproduced anaerobically

○ Also when glucose can not be used as an energy source, many cells turn to fat or protein as a fuel. This is until glucose levels return to normal

● Altered Size- when size changes are adaptively capable○ hypertrophy- cell and organ enlargement that occurs in response to

increased demands■ Myocardial cells increase in size/strength to pump through a

narrow heart valve○ hyperplasia- new cells are formed by mitosis to respond to increased

demand○ Atrophy- shrinking

■ most common when there is a reduced workload■ starts by gradually shutting down their specialized functions, is

done by degrading them with lysosomal enzymes in aautophagosomes

■ Apoptosis- a reduction in cell numbers by a process of self-destruction

■ process is genetically regulated■ surrounding cells slowly move into fill in the previous cells space■ commonly done when overdeveloping cells are produced for a

fetus or unneeded immune cells○ Cell Stress Proteins- happen when a shock or internal stress occurs

■ The proteins unfold and clump together to accumulate in the cytoplasm

■ The cells that are infected start to denature, to stabilize denaturing proteins to be expelled before they can form a clump while the normal try to clump quickly

○ Organelle changes- by altering its complement of organelles■ The liver has enzymes that help degrade toxic chemicals■ This production occurs only when a toxin persist to continue to

show upCell and Tissue Accumulations

● many injuries can directly or indirectly disrupt capability, as a result substances accumulate within the cell; like water

● Hydropic Change- occurs when cellular energy production is decreased, which causes the ions pumps fail to eject (Na++)

○ an increase of osmotic pressure● Fatty Change- Fat accumulates within the cell

○ cellular fat increases slowly until nucleus are pushed to the periphery of the cell

○ may rupture the cell which will cause surrounding damage■ happens often in kidney, liver, and heart

● Residual Bodies- the cell’s capacity to cope with potentially threatening bacteria or to deal with damaged organelles

○ They are derived from phagosomes, but retain when lysosomes are inadequate to to complete digestion

○ lipofuscin granule- containing undigested cell membrane lipids■ Found in neurons, liver, and myocardium

○ More and more bodies accumulate with age● Hyaline Change- a material that deposits protein and is found in damaged

arterioles, renal tubules, damaged liver cells, and neurons. ○ Pathogenesis of protein accumulation is present in the tissue with

hyalineReversible Changes: Structural

● depends on the nature and duration of the injury● the plasma membrane is quick to show effects

○ become stretched and distorted producing cytoplasmic bulges called blebs

○ could exhibit focal coiling that resemble whorled pattern relating to myelin called myelin figures

● when cellular swelling occurs changes can be seen in the golgi complex, ER, and mitochondria

○ Ribosomes can be seen floating within an injured cellIrreversible Injury and Necrosis

● are more damaged than reversible cells○ extreme distortions○ rapid inflow of sodium, calcium and water○ gaps allow vital cell constituents to escape○ fewer lysosomes

○ The largest indicator of irreversible cell injury is an altered nucleus■ Karyolysis- nuclear DNA is degraded; fades and melts into the

cytoplasm ■ Pyknosis- nucleus may shrink or condense■ Karyorrhexis- nucleus breaks up into dense fragments that

disperse in the cytoplasmMechanisms of Irreversible Injury

● damage to the cell membranes, effect permeability and cytoplasm organization

○ severe swelling from sodium influx○ large flow of calcium into the cell

■ High calcium causes protein denaturation; losing enzyme function

■ This particular effects the function of the mitochondria ○ A damaged cytoskelton could cause the cell to rupture

Cell Death● A cell can make a full recover and adapt● Cell recovers, but not normal functions● Cell death

○ at has reached ‘the point of no return’● Necrosis- the condition of cell death

○ Substantial changes occur- ■ cell broken down by endogenous enzymes and phagocytic cells

○ Lysosomes initiate chemical breakdown of cell● Coagulation necrosis- tissues become firm

○ cell proteins quickly denatured by high levels of acid and calcium ○ Lysosomal enzymes are unable to digest until phagocytic blood cells

arrive to finish breakdown● Caseous necrosis- has a pale, granular, cheese like appearance● Gangrene/ gangrenous necrosis- happen when access is gained to an area of

damage caused by reduced blood flow (ischemia)○ Putrefaction- foul-smelling gases produced○ wet gangrene- liquefaction○ dry gangrene- coagulation is sustainde

● Liquefaction necrosis- coagulation does not occur, necrotic tissue breaks down quite promptly

● calcification- persistent injury or slow developing● dystrophic calcification- calcium crystal progressively produce large masses

leading to brittleness and affected tissue● Metastatic Calcification

○ it occurs in otherwise normal, as opposed to necrotic tissue○ the deposition is a consequence of an excessive systemic calcium

level, or hypercalcemia ■ found mainly in lung, kidney blood vessels, or stomach

membraneTissue Vulnerability

● Ischemia- cns neurons are highly sensitive bc of high metabolic rate and depend on glucose as their energy source

○ underlying cause of a stroke○ while the kidney, liver and fibroblast are tolerant of this

● Intoxication- Carbon tetrachloride, is inhaled and transported to the liver○ does not affect respiratory tract, but once in the tissue it produces a a

toxic free radical● Ionizing Radition- Actively dividing cells undergoing DNA replication are

injured mostly; skin● Viral Infection- enter and then disrupt the cells from within

○ A virus attacks specific cells

Chapter 2 – Inflammation

○ All conditions that end in “itis” are inflammatory conditions○ Examples being: dermatitis, meningitis, pericarditis○ Inflammation is a complexly orchestrated response to injury that serves to

destroy the source of injury, remover the accumulated debris, and trigger the repair process.

Normal Vascularized Connective Tissue○ This tissue is known as loose or areolar connective tissue.○ Located in the dermis of the skin, mucosa lining of the G.I. and urinary tract,

epithelium of respiratory tree, muscle fibers, and lining of joint capsules.○ Relaxation of precapillary sphincters permits blood flow through portions of the

capillary bed. Metarterioles can shunt blood past the tissue when the precapillary sphincters, which regulate blood flow through the tissue, are closed. (figure 2.1)

○ Endothelial junction- two adjacent endothelial cells meet, their edges overlap and a thin layer of glycoprotein fills the gap. Mostly found in loose connective tissue. Inflammation will loosen these junctions.

○ Blood hydrostatic pressure (BHP)- pressure of blood enclosed within vessels

○ Tissue hydrostatic pressure (THP)- pressure of fluid within the tissue

○ Fluid is exchanged back and fourth based upon the blood osmotic pressure (BOP) and the tissue osmotic pressure (TOP). For example, under arteriolar dilation, BHP predominates, forcing more fluid through the capillary.

Acute Inflammation○ An increased flow without increased permeability, such as an active muscle,

moves more fluid to the tissues, but this fluid simply represents an increase in volume and not a change in the nature of the fluid. Such a fluid is called a transudate. It has relatively little protein. The opposite is called exudate, which

forms with increased permeability at the capillary is rich in proteins and cells, which drastically reduces BOP and increases TOP.

○ Why is the accumulation of fluid and plasma proteins important at site of an injury?

1. Dilution of toxinsa.Preventing any further damage substances might do

2. Increased pain, caused by swellinga.The pain forces limited use, helping to prevent more damage

3. Presence of antibodiesa.Without the body changing vascularity and permeability these antibodies would

stay in the blood; however, they don’t and they help with disease fighting.4. Proteins

a.Help amplify the injury response, kills organisms and promotes phagocytosis of organisms causing tissue damage.

Descriptive Classification○ Acute inflammation can be classified by the nature of their fluid exudates. The

more serious the injury the more fluid and proteins leave the blood○ Serous inflammation- response to mild injury, where only fluid is allowed to

escape to the intercellular spaces. Endothelial cells contract only slightly leaving protein in the blood. A good example is the watery fluid seen in the blister of a burn

○ Suppurative inflammation- more severe injury causing greater necrosis. Here neutrophils form the thick, white-green fluid called pus.

■ Cellulitis• Diffused (spread) inflammation of pus

■ Abscess• Localized accumulation of pus

■ Cyst• A fluid filled sac usually left over from inflammation

○ Hemorrhagic inflammation-Large number of red blood cells (erythrocytes) escaped due to capillary damage.

The Formation of Exudate: Cellular Factors○ Leukocyte emigration- the outpouring of large numbers of white blood cells from

the blood. Inflammation greatly increases the emigration of leukocytes, due to the changes in blood flow.

Margination● axial flow- blood flowing at normal rates

○ bloods (erythrocytes, leukocytes, platelets) move in a central column○ plasma is on the periphery flowing smoothly along endothelial lining of

the vessel

● In inflammation fluid is lost and flow rate decreases, the central column of elements enlarge and the leukocytes now lie along the periphery known as margination

Rolling, Pavementing, and Adhesion● The leukocytes now in the periphery adhere to the endothelial surface, where

they flatten○ This is important because this causes the stat of motion of leukocytes

to discontinue so it can transition to the inflamed area easierTransmigration

● The leukocytes move to an endothelial junction, this is where it squeezes past the endothelium, continuing through the cells basement membrane.

○ occurs at the endothelial gaps of post-capillary venules● diapedesis- process of emigration, the passive movement of red cells that

may occur at the same site● Two types of leukocytes

○ neutrophils- the earliest, described as polymorphonuclear cells (PMNs) multi nucleated

■ last only up to 48 hours then undergo apoptosis○ Mononuclear cells or monocytes- large and when in the tissue spaces

they are called macrophages■ longer lasting

Phagocytosis● A phagocyte must be activated and move to the problem, to attach to it.

○ It engulfs/destroys the target by releasing enzymes and toxins stored in its lysosomes.

Chemotaxis● When a phagocyte is in an inflamed tissue and encounters an increased

chemical attraction, this is chemotaxis.○ exogenous chemoattractants are both peptides and lipids.

● This occurs when the presence of specific receptors bind and trigger biochemical events, making a larger and more active phagocyte

○ Directing movements is done by rapid assembly of actin molecules Recognition and Attachment

● Opsinization- greatly enhances phagocytosis ○ opsonins are substances from the plasma that have an affinty for the

surface features of foreign particles■ leukocytes are able to respond because they contain opsonins

binding sites● once bond it is readily engulfed

Engulfment and Destruction● A phagocyte encloses around the particle while the granular-appeared

lysosomes destroy it○ once merged together lysosome numbers reduce and is said to be

degranulated● If the particle is too big (multi-cellular) it may be regurgitated into the tissue

spaces○ can happen to immune complexes exposed on the basement

membrane■ A leukocyte attempting to engulf this experiences ‘frustrated

phagocytosis’

■ Releasing toxic and degraditive substances that damage the basement membrane and surrounding cells/matrix.

● extensive tissue damage can occur● oxygen-independent- mechanisms involve the release of performed

substances that damage bacterial cell walls, disrupt bacterial replication, and produce a low pH, which may be directly toxic and may indirectly aid the function of other enzymes.

○ Restriction of bacterial mitosis by iron-binding loctoferrin○ Bacterial cell wall damage by:

■ BPI- permeability■ lysozyme-coat-digesting■ major basic protein- toxic to parasites

● Oxygen-dependent- more important than oxygen-independent, accomplished by the creation and release of oxygen free radicals: ‘singlet-oxygen’

○ Halogenatin is the most potent bactericidal agent produced by neutrophils

■ focuses on the destruction of engulfed organisms● In regruiated or frustrated phagocytosis, the destruction is turned on the host

tissues (bystander injury)Bacterial Defenses

● Some bacteria have evolved a variety of defenses against phagocytosis○ exotoxins killing leukocytes or inhibit chemotaxis○ slimy coat, which opsonins have a difficult time binding to○ touch capsules○ shedding substances that bind opsonins○ producing cytotoxins that protect against enfulfment

Defects in Leukocyte Function● In the chain of events at any point will impair host defenses, causing a defect

○ Leukocyte defects are often chronic, involving bacteria with low infection potential

■ Chronic granulomatous, disease of childhood-genetic defect in phagocyte killing due to impaired production of oxygen free radicals

■ Chediak-Higashi syndrme, defects in bot phagocyte motility and degranulaton, often leading to early death

■ Diabetics- defects are caused by circulatory problems, preventing inflammatory cells to be delivered to the inflammation site

■ Drugs (steroids, morphine, tetracycline, and chloamphenicol)Chemical Mediation of Inflammation

● Injury initially causes certain chemical substances to be produced or release at injury site to cause acute inflammation

● Initiators- trigger the same vascular or cellular responses of inflammation events (nonspecific)

○ signal a risk of cellular injury● Chemical mediators- indirectly achieved from initiators

○ may have multiple responses but ultimately achieve an inflammatory response

○ works in a positive feedback loop ■ tend to be short lived signals

■ A single occurrence (bee sting) can be resolved quickly ● But several (bee stings) can cause an allergenic reaction

(anaphylactic shock) ● Can be a long term issue which triggers low levels, but

severe damage can occurCell-Derived Mediators

● Histamine- familiar to allergy suffers, decreases vascular permeability○ antihistamines reverse this process by inducing venule endothelial cell

contraction (allows exudate to form)■ Histamine is released from mast cells and platelets

● Mast cells are leukocytes that have a specialized location/function. Lie along the skin, GI tract mucosa, an respiratory tree

○ They are the first line of defense against many pathogens

● What triggers degranulation? (the release of mediators from preformed granules)

○ Cold, heat, trauma, and encounters with foreign antigen■ Dealing with parasites and worms■ Downside they are triggered by allergens which produce

immediate symptoms● swelling and mucous secretion

○ To be effective antihistamines has to be taken prior to exposure of allergen

● Serotonin- released from platelets after encountering collagen in the basement membrane

○ same effect as histamine● Eicosanoids- products of the metabolic transformation of the membrane

phospholipid-derivative arachidonic acid (AA)○ Slow compared to histamine and serotonin

■ All leukocytes and mast cells produce AA■ AA passes through either of two enzyme-mediated pathways

● Lipoxygenase-route producing leukotrienes○ Leukotrines take up the role of increasi vascular

permeability left of from histamine and serotonin○ some produce vasoconstriction○ trigger leukocyte adhesin and chemotaxis

● Cyclooxygenase- route producing prostaglandins and thromboxans

○ prostaglandins- produce vasodilation and enhancing the effect of other mediators

■ There are two ways that chemicals can interrupt the production of eicosanoids

● Corticosteriods- shut off the supply of AA○ counted on to shut down an inflammation if it gets

out of control (like in asthma)● Nonselective cyclooxygenase (COX) inhibitors- inactivate

only the pathway that leads to the productions of prostaglandins and thromboxanes

○ Acetylsalicylie acid (ASA), acetaminophen, and NSAIDS are COX inhibitors

○ COX-1-the covering mucus for the GI tract and responsive rfusion of the kidneys

○ COX-2- inflammatory response, pain, and fever■ Nitric Oxide (NO)- an important signal in the nervous system, the

vasculature, and inflammatory response● Vasculature- potent vasodilator● nervous system- a neurotransmitter-like role and

participates in the targeted management of local perfusion

● Inflammaotry response- is activated macrophages and perform many functions

○ makes it harder foeukocytes t roll and attach, reducing the release of histamines/serotonin

○ It has a favorable antibacterial effect■ if too much person can go into shock

■ Platelet-activatin factor (PAF)- released by basophils and mast clees, macrophages, neutrophils,platelets and endothelial cells; causes platelets to aggregate and degrnulates

● but also modulates vascular tone and facilitates other inflammatory processes

Plasma-Derived Mediators● Cascade- formed at the end of a sequence of activation steps

○ a postive feedback system○ a number of inactive proteins circulate in the plasma

■ an initial activation event occurs to activate a protein, then a second, third..etc

○ four interrelated cascades can be triggered by a protein known as Hagmen factor (Clotting factor XII):

■ blood coagulation and fibrinolytic cascades function in inflammation and blood loss prevention

■ kinin-restricts its role to mediating inflammation● bradykinin- contributes to the pain of inflammation

○ tension and pressure from damaged site○ lowered pH and potassium from damaged cells

■ complemet-linked to inflammation and the immune system● consists of 20 circulating proteins● Sequential activation produces a complex of five protien

caled the membrane attack complex (MAC)○ Destroys invading microorganisms by punching

holes in their membranes○ anaphylatoxins-act as mediators of inflammation,

dilation, permeability, chemotaxis, phagocytosis, an histame release from mast cells

■ triggered by microorganisms surface and antibody conjuntion in defensive role of the immune system

● are done in rapid dramatic fashion○ drops suddenly ending the acute inflammation

■ mediator is exhausted or terminated■ cascades are triggered that reverse the

mediating cascade■ anti-inflammatory■ antioxidant■ antiproteolytic agents to former injury site

○ The result quenhes acute inflammation, analogous to the process that limit coagulation of blood

■ sets stage for healing process■ Antibody- plasma-derived mediator that is not formed by a

cascade● a key immune system element that may be an initiator

that activates the complement cascadeSystemic Effects of Acute Inflammation · Familiar effects of systemic inflammation include: fever, loss of appetite, very deep sleep, rapid weight loss, residual weakness.· Lymphadenitis- swollen lymph nodes· Lymphangitis- a bacterial infection at lymph nodesTemperature· Application of cold to swelling causes vasoconstriction to prevent heat loss, the reduced blood flow has the effect of reducing formation of fluid exudate and swelling is relieved. Application for more than ten minutes will trigger the mast cells to degranulate therefore worsening the inflammation. Applying cold will help build up phagocytes and then applying heat will active phagocytosis.Elevation & Pressure· Fluid exudate and swelling can be reduced because blood flow is slowed down to gravity. Same for pressure, pressure can prevent exudate from forming by increasing the pressure in the tissues, so the fluid is prevent from leaving the blood vessels.Drug Therapy· Antihistamines- drugs that block the action of histamine at its blood vessel receptors.· By blocking cyclooxygenase activity, agents like ibuprofen and aspirin block prostaglandin synthesis and removes an important inflammatory mediator. Chronic Inflammation· Chronic inflammation is considered to be after six weeks duration· Over time fluid exudate diminishes and cellular response assumes dominance.· In this case the attack of an agent and the attack of our defense are equally strong and never able to overwhelm one another.

Chapter 3: FeverI. What is fever?A. Elevation of the body temperature above its normal rangeB. Also known as pyrexiaC. Associated with disease and infectionD. Fever represents an upward adjustment of the temperature level that the system seeks to establish and maintainII. Normal ThermoregulationA. Normal oral temperature=36.7oCB. Temperatures normally don’t vary more than ±0.5 oCC. Rectal temperature is the most accurate form1. Core temperature gives you a more true reading2. Oral temperature is affected by ingestion of cold or hot substances or by breathing patternsD. Temperature is closely regulated because temperature changes can affect cellular functions1. Warm-blooded animals and heat conservation2. A fever of 43 oC results in death within hoursE. Maintaining a normal temperature is possible by balancing heat production against heat loss1. Heat production: energy is constantly produced and released from living tissues in the form of heata. At rest, the liver and heart are the source of most body heat2. Heat loss: achieved through heat delivery to the body surfaceIII. Mechanisms of Heat Production

A. Shivering—a patterns of rapidly alternating skeletal muscle contractions that produce no skeletal motionB. Non-shivering Thermogenesis1. Thyroid hormone: tells muscles to stimulate metabolism and generate heat2. Brown adipose tissue: fat that is not intended to store lipids, but to break down triglycerides through the Kreb’s Cyclea. Produces only heat, no ATPb. Present in babies and hibernating animals to keep body temperature at within normal ranges3. Vasoconstriction and vasodilationIV. Mechanisms of Heat LossA. Radiation—heat energy moves direction away from the warm skin surface1. Example: feeling the heat of a stove top without touching itB. Evaporation—water at the skin surface is converted from liquid to gas1. The process consumes heat from the surrounding skin2. Accounts for 30% of heat loss at restC. Conduction—direct transfer of heat by physical contact between the body and a cooler surrounding medium1. Accounts for up to 70% of heat loss from the skinD. Convection—heat is carried away by movement of the air or water surrounding the body1. Example: immersion in waterV. Regulation of Heat LossA. Types of Regulation1. Reflex shivering2. Thyroid hormone (TH)3. Behavioral Responses4. Changing body position, adding layers or blanketsB. Skin regulation1. Dermal blood flowa. When blood is moved near the surface, more heat is lostb. When blood is moved farther from the surface, less heat is lost2. Sweat productiona. Changes in sweat production cause greater or less heat lossb. Insensible water/heat loss: loss of heat by evaporation form the skin and lungsC. Negative Feedback Control of Body Temperature1. The temperature control system has one or more effectorsa. Effectors= components that can respond to bring about changes in temperatureo Major Effectors: dermal arterioles, sweat glands, skeletal muscle

2. Temperature Integration Center (TIC) decides how to regulate temperature based on information sent through the anterior hypothalamusa. Information is sent via sensors (types of thermoreceptors) which are sensitive to temperature changesb. The system maintains the particular variable close to a certain value (set point)3. Loss of homeostatic control

a. Wet clothing, intoxication (impaired judgment and neural function), competitive exertion, abnormally low body fat, dehydration, illnessb. If it’s too hot, what mechanisms are used?o Vasodilation

o Sweat production

*parts of a negative feedback loopD. Failure of Normal Thermoregulation1. Hyperthermia (when you’re too hot!)a. “Loss of homeostatic control resulting in rising core temperature”b. Increases metabolic rate of tissues (more heat is produced)c. Classic heatstroke: occurs in hot, dry environments when body temperature exceeds 105 oFo Signs: hot, dry skin

o This causes: delirium, seizures, tachycardia (increased heart rate; ≥120 BPM when at

rest), dehydration, anhydrosis (no sweating)o The thermoregulatory system has shut down

o You are now pumping hot blood up to the brain, which induces delirium and seizures

d. Exertional heatstroke: occurs in athletes whose intense activity in a hot environment generates heat faster than it can be clearede. Malignant hyperthermia of anesthesia: when a genetically predisposed person is given certain anesthesia/muscle relaxants, then develops muscle rigidity and severe hyperthermiaf. Heat exhaustion: a milder form of hyperthermia2. Hypothermia (when you’re too cold!)a. “Prolonged or extreme exposure to cold”b. Mild hypothermia: the core temperature is 90-95 oFo This causes: intense shivering and muscle cramping, which may impair self-rescue efforts

c. Severe hypothermia: the core temperature is <90 oFo This causes: shivering stops (it is no longer effective, pulse and respiratory rate slow (to

avoid heat loss), BP drops, impaired judgment, altered consciousness, and a sense of euphoria*highly maladaptive behaviorso “After drop”= continuing drop in core temperature after salvage mechanism begin

§ Muscle activity is returning cold blood to the body cored. Heat loss is 30x faster in water than in air via convectionVI. FeverA. Fever is most commonly a prominent manifestation of inflammation1. “Febrile”=a feverish patient2. It is part of a broad, integrated acute phase reactiona. The hypothalamus orchestrates endocrine responseso Release of glucocorticoids (stress response)

o Decrease in vasopressin (Anti-diuretic hormone)

o Increased HR and BP

o Blood is directed towards the body core

o Higher-order behaviors are triggered

§ Chills, which prompt warmth seeking, appetite loss, and malaise3. Elevated temperature DOES NOT suggest a defect in the temperature-regulating control systemo The system is functioning properly, but a new set point has been generated by the TIC

o This causes: pallor (from vasoconstriction in skin) and chills (from vasodilation in body

core to redirect blood flow)4. A pyrogen is a fever-causing substancea. Endogenous pyrogens (EP) cause the set point to be raisedo Caused by interleukins from macrophages and monocytes

§ Mononuclear phagocyte groupo Can directly bind to the vagus nerve, which innervates all inner organs (“gizzards and

innards”) and sends a signal to the anterior hypothalamusb. Exogenous pyrogens are from bacterial endotoxinso They may not directly act as a pyrogen, but the toxic secretions have the same effect as

EPsB. The Role of Fever1. Positive Aspectsa. Some viruses and infectious agents are temperature-sensitive, so the spike in temperature may kill/denature the agento This is an adaptive response, as long as the temperature is below 105 oF

b. Fever causes enhanced immune performanceo Leukocytes and antibodies are more effective

o Phagocytosis is more efficient

2. Negative Aspectsa. Fevers greater than 105 oF can compromise cardiac functiono The fever increases cardiac workload (increased HR and neural oxygen uptake)

o Warmer tissues increase metabolic rate, thereby producing more heat

o Risk of brain damage

o Head injury can cause the hypothalamus to not work properly, sending fever levels up past

the 105 oF max for safety3. Fever of Unknown Origina. Fever of at least 38.3 oC (101 oF) continues for at least 3 weeks without a causeb. Causes:o Infection (31%)

o Malignant tumor (21%)

o Collagen-vascular disease/autoimmunity (14%)

o Other (22%)

4. Drugs and Fever (Antipyretic Therapy)a. The most common drugs used to reduce fever are Aspirin and acetaminophen (Tylenol)o Both block prostaglandin production

§ Decreases the set point back to normal§ Activates heat loss mechanisms**Cool the brain, then the body**

Chapter 4: HealingI. Healing: the restoration of structure, strength, and sometimes functionA. Example: scarringB. Inflammation bridges from injury to healing

1.Benefit: this prevents further damage, cleans out infection and debrisII. Components of the Healing ProcessA. The healing process provides for the replacement of lost tissue through the proliferation of

adjacent undamaged tissueB. Most organs are formed of parenchyma cells1.Parenchyma: cells that are bound together and supported by connective tissue and blood

vessels that combine to form the stromaC. Regeneration1.Regeneration occurs when tissue is replaced from parenchyma2.Cells lost through injury may be replaced by mitosis of the adjacent parenchymaa. Regeneration offers the ideal response to tissue loss because the new tissue assumes

normal functions3.Not all cells have the same regenerative capacitya. Labile cells: must divide continuously to replace cells that are constantly being depleted by

normal processes1) Examples: epithelia of the skin, mucous membranes, duct linings, red bone marrow2) Regeneration involved accelerating the normal mitotic rateb. Stabile cells: the cells slowly divide after adolescence1) The cells are able to function normally throughout life (high mitotic rates are not required)2) Examples: glands, the liver, osteoblasts, smooth muscle fibers, vascular endothelium3) Regeneration involved increasing the mitotic rate, forming an organized pattern dictated by

the remaining undamaged stroma§ When the stroma is disrupted, there is a disorderly regeneration process, which leads to

functional deficiencyc. Permanent cells: lose all mitotic ability soon after birth, never to be regained1) This results in functional loss if tissue is damaged2) Examples: nervous tissues, cardiac and skeletal muscle3) Cells are replaced by scar tissueD. Repair1.Repair occurs when fibrous CT is laid down to restore the strength and structural integrity of

damaged tissues that cannot regeneratea. Fibrosis=scar formation from collagen-rich replacement tissue2.Collagen formationa. Fibroblasts form the fibers1) They are resistant to damage and are likely to survive at the injury siteb. Procollagen is secreted; outside of the cell, these fibers are enzymatically altered to that they

link together to form long filamentsc. These long filaments join together to form thicker collagen fibers, which join to form collagen

fiber bundles

d. Cells have great tensile strength1) Cross-linking allow the fibers to resist being pulled apart2) The bundles realign along the injury site to provide the greatest strength3.Scarringa. The process begins in the ECM, which contains elastic fibers and glycoproteins1) The glycoproteins contain a small number of sugar unitesb. Proteoglycans have a dominant carbohydrate component (aka mucopolysaccharides)c. The ECM directly contributes to the formation of a strong and well-anchored scar1) When damage occurs, blood floods the area and plasma fibrinogen is converted to fibrin§ Fibrin forms a mesh that entraps blood cells and tissue debris (clots)2) Organization=the elimination of the clot by phagocytosis and its replacement by scar tissue3) Water follows, hydrating the tissuesE. Revascularization (Angiogenesis)1. Revascularization is the production of new blood vessels to supply and drain the damage sitea. This occurs in the loose exudate during regeneration and repairb. Granulation tissue: new capillaries grow into the exudate1) The exudate takes on a pink and granular appearance2) The tissue is a transition material for fibrosisc. Endothelial buds form on capillaries, growing out until they reach another bud and fuse into a

new capillary1) Cells in the bud vaculolate to form lumen (This is called canalization)2) The new capillaries are leaky and highly permeable, which accounts for continued swelling

seen after an injuryF. Surface Restoration1.Surface restoration is the regeneration of the protective epithelium that covers the body and

organ surfacesa. This occurs because epithelial cells are labile1) There is a zone of active mitosis near the wound edgeb. Abrasion=a scraping injury of the skin, where only the epidermis is lost1) Sliding of epithelial cells occurs at the surface of the underlying dermis (Epithelial migration)§ The cells secrete new basement membranes§ Damaged hair follicles and skin glands cannot regenerate to form functional replacements

because they are stabileIII. Wound HealingA. Primary Healing (Healing by First Intention)1.Healing of an incision or small cut/abrasiona. Damage is minimal and the wound edges are close to each other2.Clotting serves to limit further blood loss and to seal the wound from dehydration and infective

microorganism infestationa. The surface of the clot dries up, forming a scabb. Phagocytes quickly work to clean the wound, loosen and digest the clot1) Hemoglobin released from entrapped red cells is broken down to yield pigments that

contribute to the early discoloration sometimes seen at the wound site

3.As surface restoration proceeds, pigment-producing melanocytes cannot regenerate and so they are not replaced (this is why scars are not the same color as the surrounding skin)

4.Strength of fully healed skin never reaches preinjury levelsa. Maximum strength is 70-80% of normalB. Secondary Healing (Healing by Second Intention)1.Healing of a wound whose edges are not closely apposeda. These wounds produce more debris and take longer to heal2.The same steps are taken as in Primary Healing, but with two added factorsa. There is a larger amount of granulation tissue needed to fill the wound gapb. Wound contraction=the wound edges draw towards the center1) Reduces size of the gap that the granulation tissue must fill2) Reduces the area that the new epithelium most restore3) Contraction depends on myofibroblast cells that exhibit contractile capability while

resembling a fibroblast§ They anchor themselves to other cells or fibrous structures at the wound margins§ They slowly contract, drawing in the edges to reduce wound sizec. Original wound shape is different from resulting scar shape1) This is due to the wound contraction process2) Myofibroblasts contract at right angles to the wound’s margin§ Square wound=X shaped scarIV. Healing: The Major TissuesA. Connective Tissues*Limited blood supply=prolonged healing process1. Bonea. Osseous tissue has well-developed powers of regenerationb. While bone is fractured, new bone tissue is formed and restores the original structure and

strength at the site of damagec. Occurs in three stages1) Step 1: Removal of clotted blood, bone fragments, and other tissue debris§ Bleeding into the gap between the bone ends and surrounding muscle mass§ Granulation tissue forms and becomes organized§ Capillaries develop from undamaged vessels§ Osteoblasts are activated and migrate to the damage site2) Step 2: Laying down collagen deposits and cartilage§ Fibrocartilaginous mass spans the break and provides early stabilization of the fracture; forms

osteoid§ Osteoid= “soft callus”§ Ossification occurs by osteoblasts to form spongy bone (hard callus)1. This is weak and locally enlarges the bone at the fracture site3) Step 3: Remodeling of the hard callus§ This restores the characteristic architecture of normal bone§ Osteoblasts and osteoclasts build up and break down the hard callus, modeling the bone to

finally restore its normal structure§ Then periosteum restoration occurs

2.Tendon/Ligamenta. This is usually successful where relatively regular edges can be closely approximated and

tightly suturedb. Fibroblasts then produce densely-packed collagen bundles to restore tensile strengthc. Scar tissue forms in any irregular, roughened surfaces1) This makes for a weaker union with less tensile strength and reduced functional capacity3.Cartilagea. Heals by fibrous repairb. Scar tissue is supplied by fibroblasts from perichondriumc. Scarring can produce some function loss4.Adipose Tissuea. The precursor cells are able to produce new replacement tissue if damage occursB. Epithelial Tissue1.Epithelia are labile2.Regeneration occurs at body surface, mucous membranes, and many other epithelial surfacesa. EXCEPTION: epithelium of respiratory surface1) Regeneration can occur of the damage is superficial, but NOT if the basement membrane is

damaged or if the ECM is disrupted§ This would lead to scar formationC. Glandular Tissue1.Most glands are formed of stabile tissuea. EXAMPLE: liver1) Complete restoration has been noted even when 90% of the liver has been

damaged/removed2.When tissue damage is extensive, regenerated tissue may vary from the norma. Causes some functional lossb. EXAMPLE: kidney1) Glomerular or Bowman’s capsule cells are unable to be replaced3.Severe injury can damage ECM, stroma, and parenchymal cellsa. Lost tissue is replaced by a smaller volume of dense scar tissueb. Produces an irregular surface pattern1) EXAMPLE: glomerulonephritis of the kidney (Figure 4.15)4.Exceptions include:a. Parathyroid glands possess minimal regenerative capacityb. Adrenal medulla and posterior pituitary: unable to produce new functional cells1) Due to their derivation form nervous tissue, which is permanentD. Nervous Tissue1.Neurons are permanent cells (no mitosis is possible after birth)a. Damaged neurons are replaced by gliosis (the proliferation of neuroglia)b. Provide support, phagocytosis, and repair functions similar to white blood cells2.In CNSa. If the cell body remains intact, some initial regeneration of axons may occur1) After 10-14 days, the proliferating glial cells form a scar-like mass that blocks any further

growth

b. No function can be restored by this partial and inadequate axon regeneration3.In PNSa. When only part of a myelinated neuron process is lost through damage, the lost portion can

regenerate if the supporting CT and Schwann cells remain intact along the original path of the neuron process

1) Schwann cell is more resistant to injury than is the neuron processb. A tuft of newly formed sprouts grows out of the proximal end of the process1) This pattern is relatively slow and may take weeks to complete2) It cannot replace any specialized sensory receptors3) Results in loss of sensationc. As long as the endoneural tube is intact, axons will regenerated. Traumatic neuroma: separated nerve endings result in the distal processes to degenerate1) New regenerating processes emerge from the severed nerve stump and grow into the scar

tissueE. Muscle Tissues1.Skeletal and cardiac muscle are permanent2.Healing is accomplished through fibrous repair (scarring)a. Loss of functionb. Remaining cells increase in size and strength3.In smooth muscle, mitotic capability is limiteda. EXCEPTION: Uterine wallV. Complications of HealingA. Contracture1.When damage is extensive, newly formed collagen demonstrates exaggerated wound

contraction2.This can also lead to tissue distortion and mobility limitsa. EXAMPLE: widespread skin burns1) Cause substantial disfiguration3.In repair of damage to the walls of tubular organs, stricture (narrowing of organ’s lumen) occursa. Consequences: normal motion of the organ contents is slowed or stopped1) This is the cause of much infertility in womenB. Adhesions1.Result of the organization of inflammatory exudate between serous membranesa. Produces a firm union of the two membranesb. Restricts movement1) EXAMPLE: heart, lung, or abdominal organs develop adhesion after surgeryC. Dehiscence1.The breaking open of a healing wounda. Cause: pressure applied to the healing tissues interferes with the development of normal

strengthb. EXAMPLE: abdominal wall2.Risks:a. Exposure of the abdominal contents to infectionb. Loop of intestine is squeezed into the open wound, threatening blood supply

c. Herniation=displacement of an organ from its normal positionD. Keloids1.Irregular masses of scar tissue that protrude from the surface of the skina. Result from overproduction of dermal collagen during healingb. Could be due to excessive release of a particular growth factor, TGF-BE. Proud Flesh1.Overproduction of granulation tissue2.Interferes with surface restorationF. Suture Complications1.At the surface, where the suture material enters the skin, the epithelium is interrupteda. This stimulates mitosis and migration, but the cells cannot spread across the sutureb. Instead, they migrate into the dermisc. When the sutures are removed, most of the new epithelium is carried off with the suture2.What can go wrong:a. Keratin can be sealed within the suture tract, deep within the dermisb. This causes a pronounced fibrosis (scarring) in the dermisc. This explains the more prominent scarring seen at points where sutures have passed

through the skinG. Therapy1.Radiation and chemotherapya. Suppress mitosis of cancer cells AND regular cell healing2.Inflammatory Drugsa. Interfere with protein synthesis, wound contraction, and regeneration of new epitheliumVI. Requirements for HealingA. Clearance of Debris1.Decreases likelihood for infection and healing delayB. Immobility1.Movement near wound edges delays healinga. Interferes with the joining of tissues across the damaged area2.Non-Union (Fibrous Union)a. Fibrocartilaginous mass resembling osteoid is formed, but does not ossifyb. This tissue is much weaker3.Nerve and tendon regenerationa. Accurate alignment is necessaryC. Blood Supply1.Delivery of oxygen to healing area2.Many healing problems in elderly adults is a result of inadequate blood supplyD. Nutrients1.Dietary protein deficiency will depress the healing response if prolonged2.Vitamin C=collagen formation3.Copper=cross-linking with collagenVII. Control and Regulation of HealingA. Growth factors1.Promote growth

B. Growth Inhibitors1.Oppose growthC. Together, these regulate the processes vital to normal healing1.Fibroblast migration, vessel formation, and collagen formationD. ECM1.Affect proliferation and migration and differentiationE. Physical Contact and Barriers1.When dividing cells contact each other, mitosis stops (contact inhibition)a. This only occurs when the cells coming in contact with each other are the same type of cell