Patho Exam 2

first line of defense

• nonspecific

• mechanical barriers (unbroken skin + mucous membranes)

• secretions (tears, sweat, gastric juice)

second life of defense

• nonspecific

• phagocytosis, inflammation

• interferon (antimicrobial protein - destroys microorganisms)

third line of defense

• specific

• production of specific antibodies

definition of inflammation

• Protective mechanism + important basic concept in patho

• disorders are named ending in -itis

• normal defense mechanism

• signs/symptoms are a warning for a problem (problem could be hidden)

• not same as infection (infection is one cause)

causes of inflammation

• direct physical damage (cuts, fractures)

• caustic chemicals (acids, cleaning agents)

• ischemia, infarction

• allergic reactions

• foreign bodies (splinter, glass)

• infection

acute inflammation

• process of acute is same, despite cause

• chemical mediators are released in injured tissues (affect blood vessels + nerves in damaged area)

• mediators initiate sequence of events in vascular/cellular phase

summary of events in inflammation

1. release of chemical mediators

   1. release of bradykinin from injured cells - activates pain receptors

   2. mast cells + basophils release histamine

2. capillary dilation + increased blood flow

   1. chemical mediators (histamine/bradykinin) cause vasodilation + increase capillary permeability

3. chemotaxis to attract phagocytes: neutrophil + monocytes arrive to injury site

   1. neutrophils + macrophages phagocytize bacteria

vascular phase of inflammation

involves series of changes in local blood flow + vascular permeability

• brief vasoconstriction and clotting

• vasodilation triggered by chemical mediators increases blood flow to injury site: hyperemia

• increased vascular permeability + leakage of exudate (fluid - exudate - contains important proteins essential for fighting infection + healing process)

cellular phase of inflammation (incl def of chemotaxis)

cellular phase is the 2nd major step - involves chemotaxis: recruitment + activation of phagocytes

1. rolling + margination

   1. phagocytes line up along the inner surface of the blood vessel wall

2. adhesion

   1. phagocytes bind tightly to adhesion molecules

3. transmigration

   1. diapedesis: squeezing through the tight gaps in vessel wall

4. phagocytosis

   1. neutrophils + macrophages engulf + destroy pathogens

histamine

• from mast cell granules

• immediate vasodilation + increased capillary permeability to form exudate

cytokines

• T lymphocytes; macrophages

• increased plasma protein, ESR

• induce fever, chemotaxis, leukocytosis

leukotrienes

• from arachidonic acid in mast cells

• later response: vasodilation + increased capillary permeability; chemotaxis

prostaglandins

• from arachidonic acid in mast cells

• vasodilation, increased capillary permeability, pain, fever, potentiate histamine effect

kinins

• activation of plasma protein (kinogen)

• vasodilation, increased capillary permeability, pain, chemotaxis

2 pathways of releasing arachidonic acid

lipoxygenase

• synthesize leukotrienes

cycloxygenase

• synthesize prostaglandins

local manifestations of inflammation

redness/warmth

• caused by increased blood flow to damaged area

swelling

• caused by increased capillary permeability (shift of protein and fluid into interstitial space - development of exudate)

pain

• increased pressure of fluid on nerves: release of chemical mediators (bradykinins)

loss of function

• edema may interfere with function

technical terms for local manifestations of inflammation

rubor → redness

tumor → swelling

calor → heat

dolor → pain

functio laesa → loss of function

exudate

• fluid that leaks from capillaries into interstitial spaces during inflammation

• classified according to cause and infection type

types of exudate (5)

• serous

• hemorrhagic

• fibrinous

• membranous

• purulent/supparative

serous exudate

• watery, made primarily of fluid, some proteins, + WBCs

• ex: blister/vesicle (watery)

hemorrhagic exudate

contains significant amount of RBCs due to damage or rupture of blood vessels

fibrinous exudate

contains large amounts of fibrinogen + cells; form a thick and stick meshwork

membranous exudate

• develop on mucous membrane surfaces, forms grayish-white membrane

• made of necrotic cells enmeshed in a fibro-purulent exudate

purulent/supparative

• contains large amount of pus

• thick, yellow-green; composed of leukocytes, cell debris, + microorganisms

systemic manifestations of inflammation

fever (pyrexia) + malaise, headahce, fatigue

fever

pyrexia - common if inflammation is extensive; triggered by release of pyrogens

• leukocytes release pyrogens - interleukins (IL) + tumor necrosis factor (TNF)

• pyrogens reset thermoregulatory center: increase set point to activate heat-conserving + heat-producing mechanisms: vasoconstriction, shivering, increased metabolism

malaise, headache, fatigue (feeling unwell)

interleukins (IL) + TNF affect CNS - lethargy

course of fever

1. release of pyrogens in circulation

2. reset hypothalamic control - high

3. body responses that increase body temperature

   1. shiver

   2. vasoconstriction

   3. inc BMR

   4. inc HR

   5. curl up body

4. body reaches new high temp

5. treatment to remove pyrogens

6. reset hypothalamus to normal

7. body responses that increase heat loss activated

8. body returns to normal temperature

intermittent fever pattern

on/off consistently (break/come back), above normal/back to normal

sustained fever pattern

consistent fever over days/hours; little variation; remain above normal

remittent fever pattern

rever raises/lowers consistently (doesn’t break); remain above normal but fluctuates

relapsing fever pattern

a fever that returns after a period of no fever

lab tests - leukocytosis

show increased WBC count

• leukocytosis-inducing factors stimulate bone marrow activity + promotes release of leukocytes

lab tests - erythrocyte sedimentation rate

increases

• increased plasma proteins cause RBC to settle faster

lab tests - differential WBC count

% of each type of WBC in blood

• helpful to distinguish between bacterial + viral infection (ex: lymphocytes = most likely viral)

lab tests - circulating plasma proteins

increase

• liver makes C-reactive protein (CRP): normally not in blood

• CRP attaches to bacteria or injured cells, functions as an opsonin

chronic inflammation

• inflammation lasting 2 weeks or longer

• often related to unsuccessful acute inflammatory response

• vascular phase decrease: less swelling + exudate (decrease of local manifestations but increased tissue breakdown)

• more cell infiltration = presence of lymphocytes, macrophages, + fibroblasts (cause more tissue destruction, more fibrous scar tissue)

• granuloma may develop around foreign object

acute inflammation

self-limited + short duration

exudate formation, transmigration of neutrophils + monocytes

chronic inflammation (characteristics)

self-perpetuating + lasts a long time

• infiltration by mononuclear cells (macrophages) + lymphocytes

• proliferation of fibroblasts: multiply + migrate into injured area

• fibrosis: scar formation - fibroblasts produce new CT

granuloma

cluster of immune cells that forms when body attempts to wall off a foreign substance or an infectious agent that it can’t eliminate

• macrophages form giant + epithelioid cells to wall off + isolate area

• granuloma → giant + epithelioid cells surrounded by lymphocytes

  • granuloma associated with foreign bodies (splinter, suture)

  • granuloma associated with microorganisms (TB, syphilis - latent)

potential complications of inflammation

infection

• microorganisms can more easily penetrate edematous tissue

  • some microbes resist phagocytosis

  • inflammatory exudate also provides an excellent medium for microorganisms

skeletal muscle spasm

• protective response to pain

deep ulcers

• result of severe/prolonged inflammatioon

  • cell necrosis + lack of cell regeneration

3 types of body cells

labile, stable, permanent

labile cells

continuously multiply/divide to replace lost/damaged cells (ex: skin, blood cells)

stable cells

only divide/regenerate bc of injury or increased demand; divide until growth ceass

ex: hepatocytes, lymphocytes, bone cells

permanent cells

cannot replicate (stay in G0) - must do fibrosis

ex: neurons, cardiac muscle

3 types of healing

resolution, regeneration, replacement/fibrosis

resolution

damaged cells recover (minimal tissue damage - returns to original structure/function)

regeneration

damaged tissue replaced with functional cells

ex: epidermis regenerate after superficial injury

replacement/fibrosis

replacement of destroyed tissue with scar tissue (nonfunctional)

scar tissue: made primarily of collagen to restore strength of tissue but not function

fibrosis

tissue incapable of regenerative activity, severe acute/prolonged inflammation resolves by scarring (ex: myocardial infarction replacement of damaged cardiac muscle with fibrous scar)

wound healing

objective of healing process is to fill gap made by tissue destruction + to restore structural continuity

primary intention healing

small, clean wound

wounds that heal under conditions of minimal tissue loss

secondary intention healing

great loss of tissue with contamination

wounds that require a great deal more tissue replacement

4 stages of wound healing

coagulation, inflammation, proliferation, remodeling

coagulation

activate platelets, fibrin mesh of blood clot forms

fibrin stabilizes clot and forms a temporary framework for healing

inflammation (wound healing)

increased blood flow

neutrophils arrive first and remove bacteria + damaged tissue

macrophages follow + continue cleaning the wound while releasing growth factors

proliferation (wound healing)

new tissue begins to form

• fibroblasts proliferate and produce collagen + extracellular matrix

• angiogenesis creates new blood vessels

• granulation tissue develops

• re-epithelialization restores surface epithelium

• wound begins to contract

remodeling (wound)

maturation of wound

• collagen is reorganized and strengthened

• re-epithelialization continues

• scar becomes smaller and stronger

3 complications of wound healing

complications occur when healing is slow, excessive, abnormal

1. infection (bacteria enter would + interfere with healing)

2. ulceration (wound fails to heal + remains open)

   1. common in chronic conditions such as pressure injuries and poor blood supply

3. excessive scar formation

   1. hypertrophic scar: excess collagen produces a raised scar, remains within boundaries of original wound

   2. keloid: excessive collagen forms a raised scar that extends beyond original wound margins

adhesions

bands of scar tissue joining two surfaces normally separated

what are adhesions complications of

abdominal surgery

• adhesions can form between loops of intestine or between intestine and abdominal wall

peritonitis

• inflammation of peritoneum can lead to extensive abdominal adhesions

innate immunity (specificity, 1st exposure, 2nd exposure, type of cells, things that are released)

• non-specific

• first exposure: immediate (from birth)

• second exposure: same as first time

• cell type: phagocytes: neutrophils, macrophages

• releases: chemical mediators: histamines, cytokines, prostaglandins, complement

adaptive immunity (specificity, 1st exposure, 2nd exposure, type of cells, things that are released)

• specific

• 1st exposure: delayed/must be “primed”

• 2nd exposure: immediate/robust

• type of cell: lymphocytes (T/B cells)

• releases: antibodies (IgE, IgA, IgM, IgG)

humoral immunity (antibody-mediated)

mediated by B lymphocytes (B cells), which stimulates production of antibodies that target pathogens/toxins

lymphocytes - bone marrow - B cells - go to lymph nodes - stimulated by antigen presentation - secrete antibodies, create B memory cells

cell-mediated immunity

mediated by T lymphocytes (T cells), which destroy infected/abnormal cells and coordinate immune responses

lymphocytes - thymus - T cells - go to lymph nodes - antigen presented to T cells - T helper cells bind to antigen - activate cytotoxic T cells (also secrete memory T, suppressor T)

antigens

substance that triggers an immune response in the body

self antigen

HLA proteins label cells of the individual; immune system ignores self-antigen

non-self antigen

• immune system recognizes specific nonself antigens as foreign

• development of a specific response to particular antigen

• memory cells produced to respond quickly to the antigen

antibodies

produced by plasma cells to identify + neutralize foreign antigens

antibodies bind to antigens to initiate:

• neutralization → directly block antigen

• opsonization → mark the antigen to be removed by macrophages

• complement activation → antibodies bind to proteins of the complement system, activating MAC which helps to destroy foreign cells by punching holes in their membranes

IgG antibodies

most common in blood

produced during secondary immune response (2nd exposure)

IgM antibodies

first to increase

produced during primary immune response (initial exposure)

IgA antibodies

common in secretions (tears, saliva, breast milk)

IgE antibodies

allergic reactions + parasitic infections

IgD

help to activate B cells

Major histocompatibility complex

aka human leukocyte antigen (HLA) = set of molecules displayed on cell surface

• genes responsible for coding HLA (each MHC unique)

• MHC (HLA) controls immune response through recognition of self and non-self antigens (MHC responsible for antigen presentation + lymphocyte recognition)

MHC Type I

receptors bind to CD8 (T-cytotoxic) → MHC protein is present on all cells; self-antigen

MHC Type II

receptors bind to CD4 (T-helper); MHC protein present on anti-presenting cells (activates broader immune response + involves stimulation of B memory cells)

graft

cell, tissue, organ transplanted to replace damaged tissue, categorized based on genetic relationship between donor and recipient

allogeneic

allograft

donor + recipient are related or unrelated but share similar HLA types

synergeneic

synergeneic graft

donor/recipient identical twins

autologous

autograft

donor/recipient are same person

stem cell transplant + how to make it effective + how it works

primary immunodeficiency disorders bc of deficiency in stem cells can be cured with allogeneic stem cell transplantation

• ex: SCIDS, Wiscott-Aldrich Syndrome

to be effective: bone marrow cells of host destroyed by myeloablative doses of chemotherapy

stem cells can repopulate bone marrow and reestablish hematopoiesis

transplant rejection

a condition when recipient immune system attacks a transplanted organ bc of differences in genetic markers (HLA)

hyperacute rejection

antibody-mediated immune response that occurs almost immediately (minutes to hours) after transplantation

• initiated by pre-existing anti-donor antibodies triggering a type III hypersensitivity reaction

acute transplant rejection

within first few months with signs of organ failure - may also be months/years after immunosuppression stops

• cell-mediated T-lymphocytes respond to antigens in graft (recipient T cells - cytotoxic T cells - are activated)

chronic transplant rejection

after prolonged period, from immune-mediated inflammatory graft injury - mechanism unclear

• manifested with dense fibrosis of transplanted organ

• progressive decline in organ function (happens slowly over time)

Graft versus host disease (GVHD)

GVHD after allogeneic transplants when graft cells recognize recipient antigens as foreign

• donor T cells recognize and attach HLA on host cells

• GVHD common after allogeneic bone marrow transplant

requirements for GVHD

• transplant must have functional cell immune component

• recipient tissue must have antigens foreign to donor cells

• recipient immunity must be compromised to the point that it can’t destroy donor’s cells

GVHD vs Transplant Rejection

GVHD

• occurs when immune competent donor cells transplanted into immune compromised recipients

• acute: within 100 days (skin rushes, GI symptoms)

• chronic: after 100 days (affects multiple organ systems)

Transplant Rejection

• occur when recipient immune system attacks transplanted organ

• hyperacute: mins/hours

• acute: months

• chronic: several years

Type I Hypersensitivity

immediate hypersensitivity

• allergic rxn

• rapid immune rxn that occurs within minutes of re-exposure to specific antigen (allergen)

• common types (skin rash, hay fever)

• cause (exposure to allergen, IgE development, mast cell degranulation)

Type I Hypersensitivity - atopic

localized to particular tissue/organ

• hay fever - allergic rhinitis

• atopic dermatitis/eczema - skin (urticaria)

• asthma - bronchial mucosa

• allergic conjunctivitis - eye mucosa

Type I hypersensitivity - systemic (multiple organs/entire body)

anaphylaxis

type I hypersensitivity pathogenesis

1st exposure to allergen (IgEs form) - IgEs bind to mast cells, become sensitized

2nd exposure - mast cells release histamine

• cause vasodilation, inc vascular permeability, edema

2 phases after re-exposure to allergen

initial phase

• immediate

• within minutes of allergen exposure

• release of mediators that cause vasodilation, vascular leakage, smooth muscle contraction

late

• 2-8 hours after exposure

• intense infiltration of tissues with eosinophils, lymphocytes, basophils

• cytokines and other inflammatory mediators cause persistent tissue inflammation/injury

anaphylaxis

severe, life threatening systemic Type I hypersensitivity reaction caused by widespread response to inflammatory mediators

• histamines, kinins, prostaglandins cause systemic vasodilation (if arterioles vasodilate throughout whole body - severe hypoxia)

• ACh, kinins, leukotrienes can cause bronchoconstriction (when bronchials constrict = airway obstruction)

manifestations of anaphylaxis - skin

general itch/tingle, flushing, urticaria

manifestations of anaphylaxis - respiratory

wheezing, bronchospasm, difficulty breathing

manifestations of anaphylaxis - cardiovascular

hypotension, tachycardia, dizziness

manifestations of anaphylaxis - GI

cramps, nausea, vomiting, diarrhea