Pathophysiology Flashcards
What forces govern fluid flux between the different body compartments?
Interstitial - intracellular –> osomlarity
Intravascular - intracellular –> osmolarity
Intravascular - interstitial –> hydrostatic and osmotic (Starling)
Lymphatic and intracellular –> hydrostatic + driving
What is the normal hydrostatic pressure in the interstitium?
0 / slightly subatmospheric due to lymphatic drainage
Where is the thermoregulatory control center located in the body?
Preoptic area of the anterior hypothalamus.
What generates most of the body heat and which animals have poorly developed thermoregulatory center?
- Muscular activity
- Neonatal animals
Define hyperthermia?
Define fever?
Hyperthermia: elevation in core body temperature above the normal range as a result of heat being produced or stored in the body at a rate greater than it is lost.
Fever: hyperthermia where the set point in the anterior hypothalamus has been reset to a higher temperature.
Name a few mechanisms of heat gain or loss within the hypothalamus
Heat gain mechanisms:
- Increased production: catecholamine, thyroxine, shivering
- Decreased loss: vasoconstriction piloerection, postural changes, seeking warm environment
Heat loss mechanisms:
- Panting, vasodilation, postural changs, seeking cool environments, perspiration, grooming
Describe the pathophysiology of fever
Exogenous pyrogens (ex: infectious agents, antigen-antibody complexes, tissue inflammation and necrosis, pharmacologic agents) –> activation of immune cells (macrophages, T & B cells) –> release of cytokines (endogenous pyrogens such as IL-1, IL-6, TNF-alpha) can also be produced directly by neoplastic cells –> reach the hypothalamus via circulation –> release of prostaglandins (PGE2) –> increased set point –> increased fever
What are the 3 main endogenous pyrogens and 3 other endogenous pyrogens
3 main:
- IL-6
- IL-1
- TNF-alpha
Others:
- IFN-gamma
- IFN-alpha
- IFN-beta
- TNF-beta
- IL-8
- Macrophage inflammatory protein 1
What are the 4 mechanisms of heat loss in the body
- Radiation: electromagnetic heat exchange between objects in the environment.
- Conduction: between the body and environmental objects that are in direct contact with the skin (relative temperatures and gradients)
- Convection: movement of fluid, water or air over the surface of the body.
- Evaporation: disruption of heat by the energy required to convert the material from a liquid to a gas
In active cooling, what mechanism of heat loss can be affected by applying very cold water to the patient?
Cold water can cause peripheral vasoconstriction, inhibiting radiant heat loss.
What is the hyperpyrexic syndrome?
Associated with exercise in a hot and humid environment –> evaporative cooling via panting is minimal + vasodilation to skeletal muscles with simultaneous vasoconstriction of the skin = compromised peripheral heat loss
Leads to weakness and collapse –> if temp > 41C, immediate cooling / if temp > 41.6C, may lead to permanent organ damage
Name a few pathologic and pharmacologic causes of hyperthermia
- Hypothalamic lesion
- Malignant hyperthermia - disturbs calcium metabolism, leads to myopathy with increased heat production (dantrolene is a specific and effective therapy)
- Hyperthyroidism
- Pheochromocytoma
- Opioids
What are benefits and detriments of fever?
Benefits:
- Decreases ability of bacteria to use iron (which they need to live and replicate)
- Viruses are heat sensitive and cannot replicate in warm environments
- Increases leukocyte function
Detriments:
- Increases cellular O2 consumption which may exceed delivery
- Increases tissue metabolism and water requirements
- Suppression of appetite center in the hypothalamus
- Deleterious in TBI
- Heat stroke/malignant hyperthermia –> Rhabdomyolysis, myoglobinemia, hyperK, hypoCa
Name nonspecific therapies for the febrile patient.
- NSAIDs - inhibit prostaglandin synthesis
- Total body cooling –> counter productive in true febrile patients as even with cooling, the hypothalamic set point remains high which will lead to increased metabolic rate and O2 consumption
- Glucocorticoids - block acute-phase response - reserved for when cause is non infectious
- Phenothiazine - depresses thermoregulation and causes vasodilation
How are neutrophils activated?
- Once migrated into the interstitial space, the PRRs (pattern recognition receptors) on their cellular membrane bonds to PAMPs (pathogen associated molecular patterns) on the cell wall of pathogens
- When PRRs bind to DAMPs
How do neutrophils kill pathogens (3)?
- Degranulation - release of destructive peptides and proteases
- Assembly of s ROS generator (NADPH oxidase complex) on the membrane of a phagosome –> produces an oxidative burst when activated by microorganisms
- Formation of NETs (neutrophil extracellular traps)
What cytokine is responsible for the production of neutrophils?
G-CSF (granulocyte colony stimulating factor)
Name causes of granulocyte progenitor cell depletion in animals with febrile neutropenia.
- Infectious diseases
–> Parvovirus - neutrophils are affected early because hey have the shortest half life
–> Erlichia canis
–> FIV/FeLV - increased risk of neutropenia - Medications, toxicants, radiation
–> Idiosyncratic neutropenia with methimazole, some antiepileptics, antiinfective agents, phenylbutazone
–> Chemotherapy
–> Estrogens - Myelophthisis - bone marrow failure due to infiltration of abnormal tissue –> neoplastic cells - leukaemia, lymphoma, multiple myeloma, histolytic sarcoma
–> collagen (myelofibrosis) - Cyclic hematopoiesis
–> Genetic disorder - gray Collie syndrome
Describe the pathophysiology of myelodysplastic syndrome
Clonal expansion of a mutated hematopoietic cell –> these cells mature abnormally –> apoptosis before they are released from the BM
BM appears hyperplasticity with an abnormally high number of blasts , but insufficient cells in circulation
What are the 4 main mechanisms in the pathophysiology of sepsis?
- Loss of immunoregulatory homeostatic mechanisms (cytokines from interactions of PAMPs / DAMPs and PRRs, neuroinflammatory reflex)
- Dysregulation of inflammation and coagulation (upregulation of TF, downregulation of anti-coagulant pathways, downregulation of fibrinolysis, platelet activation)
- Loss of barrier function (endothelial, microcirculatory, mitochondrial) -> increased vascular permeability, further activation of coagulation and inflammation, cryptic shock and cytopathic hypoxia
- Loss of vasomotor tone (increased NO production by iNOS)
What is cryptic shock?
The disconnect between systemic hemodynamics and microcirculatory perfusion.
What microcirculatory alterations lead to decreased O2 extraction in tissues
- Microcirculatory dysfunction (from endothelial damage)
- Heterogeneous microvascular blood flow
- Decreased functional capillary density
- Increased diffusional distance for O2
(-> cryptic shock) - Mitochondrial dysfunction
- Dysfunctional electron transport chain (cytopathic hypoxia)
What is the term used to describe dysfunction of mitochondria in sepsis?
Cytopathic hypoxia
Superoxides from neutrophils + NO combine to form peroxynitrite -> “mitochondrial permeability transition (MPT)” -> loss of H+ gradient -> inhibition of mitochondrial respiration and synthesis of ATP
Cytopathic hypoxia may lead to cellular dysfunction up to cell death
Describe how the interactions between PAMPs and PRRs contributes to development of sepsis
Part of the innate response (min to hours)
PRRs such as toll-like receptors recognize PAMPs such as lipopolysaccharide (found on gram negative cell wall) –> trigger a cascade leading to activation of NF-kB –> production of proinflammatory cytokines (TNF-alpha, IL-1, NO, ROS) + anti-inflammatory cytokines
DAMPs are released as well form tissue injury and recognized by + further activate PRRs
Describe the adaptive response in sepsis
Occurs in days post-infection
- B-lymphocytes mature into plasma cells that produce organism specific antibodies
- Antibodies attach to the antigen and mark for destruction
- Other lymphocytes migrate to thymus and mature into helper, killer or regulatory T cells
- Type 1 helper T cell secretes proinflammatory cytokines
- Type 2 secretes anti-inflammatory cytokines
- Dendritic cells are for communication between innate and adaptive systems (present antigen to T cells)
How can neutrophils directly lead to endothelial injury?
- Phagocytosis of pathogen leads to controlled production of ROS –> in sepsis ROS production may be uncontrolled –> more widespread inflammation and increased microvascular permeability
- Neutrophils also fuse granules containing protease enzymes to kill pathogens –> Excessive inflammation can lead to widespread release of protease = more endothelial damage
What is the most potent stimulus for production of TNF-alpha in sepsis?
Lipopoylsaccharide (PAMP)
Name examples of PAMPs and DAMPs
PAMPs:
- Lipopolysaccharide (Gram -)
- Lipotechoic acid (Gram +)
- Peptidoglycan (Gram +)
- Flagellin
- CpG DNA
- RNA
DAMPs:
- High mobility group box 1 (HMGB1)
- Heat shock proteins
- Histones
- ATP
- Mitochondrial DNA
What is the difference between surface TLRs and endosomal TLRs and name examples.
Surface TLRs recognize extracellular bacteria (bacterial lipids, flagellin, etc) whereas endosomal TLRs (found in the cytoplasm) detect intracellular bacteria (viral RNA, CpG DNA, mycoplasma) and viral organisms
Surface TLRs:
- TLR-1, 2, 4, 5, 6
Endosomal TLRs:
- TLR-3, 7, 8, 9
Describe the intracellular cascade following TLR detection of PAMP.
- TLRs recognize PAMPs
- Intracellular domain of TLR is activated
- Recruitment of adapter proteins (ex: MyD88, TRAM, TRIF)
- Recruitment and activation of protein kinases (ex: IRAK, Map kinase, IkB kinase)
- Activation of transcription factors (ex: NF-kB = nuclear factor-kappa B, active AP-1)
- Gene transcription - upregulation of expression of inflammatory cytokines, chemokines, endothelial adhesion molecules
What are the 2 different pathways by which LPS binding to TLR 4 can lead to cytokine production
- MyD88-dependent pathway -> activation of IRAK -> MAP kinase cascade (transcription factor AP-1) and IkB kinase cascade (transcription factor NF-kB)
- TRAM / TRIF pathway (less important)
What intrinsic regulators cause vasodilation in sepsis?
- NO-mediated:
LPS and inflammatory cytokines (IL-1, TNF) –> production of inducible nitric oxide synthase (iNOS) –> iNOS aids in conversion of L-arginine to L-citrulline –> produces NO –> production of cGMP in smooth muscle –> cGMP-mediated vasodilation –> distributive shock
+ bradykinin and thrombin increase activity of eNOS (endothelial NO synthase - constitutive)
- Prostacyclin-mediated:
PAMPs and inflammatory cytokines -> induction of COX-2 -> synthesis of PGI2 (prostacyclin) -> cAMP-mediated vasodilation - Hydrogen-sulphide-mediated:
Hydrogen sulphide synthesized from L-cysteine -> inhibits cytochrome C oxidase + activates K+ ATP channels + inhibits endothelial ACE -> vasodilation - Metabolite-mediated:
Hypoxia, reduced pH, increased lactate -> activation of K channels -> cell hyperpolarization ->vasodilation
