patho test 3 Flashcards
name the protein responsible for cystic fibrosis and the subcellular location
protein: cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP activated, ATP-gated anion
sub-cellular location: plasma membrane
describe two key functions of CFTR
- secretes chloride into the airway lumen
2. inhibits Enac
name two physiological anions of CFTR conducts
Chloride, bicarbonate
describe roles of ATP and cAMP in CFTR functional regulation
ion channel allows specific ions to flow across the membrane down the electrochemical gradient. controls the opening of the channel to the ion by gating
recognize two major pathogens in CF airway infection
staphylococcus aureus (first pathogen to infect the airway, common in childeren) pseudomonas aeruginosa (opportunistic, prevelent in adults, biofilm formation)
name the pathogen that forms biofilm
pseudomonas aeruginosa
describe ppFEV1 in the context of CF lung disease
forced expiration volume in one second. percent predicted FEV1 greater than 80% normal - evidence of pulmonary function tests
describe mucociliary clearance in airway defense against pathogens
bacteria will drop on surface and cause infection if no mucus. cilia pushes the mucus together. defense agianst the pathogens
specific defect in mucociliary clearance in CF airway
causes an exaggerated immune response of mucus plugging with airway inflammation (pulmazyme, ibprofen) and bacterial infection and colonization (antibiotics)
mechanism of action of pulmozyme
DNase cleaves extracellular DNA tor reduce mucus viscosity. pulmozyme opens the lungs by thinning the mucus. extracellular DNA -> mucus from the WBC. Major content of mucus is DNA
describe bronchietasis in CF
localized, irreversible dilation of bronchi from adverse inflammatory damage
name the tissue and cell type where CF pancreatic pathophys originates
acinar cells - synthesis and secretion of pancreatic enzymes.
name the primary anion that CFTR secretes in the pancreas
secretes bicarbonate due to low chloride
describe how CF patients develop pancreatitis
there is obstruction to the duct cells from a CFTR deficiency causes an effect on the exocrine pancreas. This affects the Acinar cells to have a synthesis and secretion of pancreatic enzymes (for digestion). These extra lipases and proteases chew on nearby tissue which causes pancreatitis.
describe the distribution of CFTR in the epithelia of the GI (villus vs crypt)
crypt is where CFTR is expressed - it is where the basolateral fluid secretion occurs - part of the distal small intestine and colon
describe the primary anion that CFTR secretes in the gut
Cl-?
the key GI pathophys of CF
impaired chloride secretion leads to intestinal obstruction and chronic constipation because of inadequate hydration in maconium ileus. the cholera toxin can couse GTPase inhibition which can cause CFTR over-activation and diarrhea because of too much cl-
describe cell types that express CFTR in the liver and gallbladder
apical membrane of the epithelia of the intra and extra hepatic bile ducts and gallbladder but NOT hepatocytes
describe how CF patients develop diabetes
The obstruction on the duct cells from a CFTR deficiency has an effect on the endocrine pancreas (where insulin/glucagon are produced . The inappropriate activation of retained enzymes has an effect on the islets of Langerhans - deficiency in this causes a deficiency in insulin secretion - causes CF-related diabetes
primary functions of the respiratory system
to oxygenate and eliminate co2
alveolar space
exchange = ventilation
unidirectional blood flow
blood flows through the lung to absorb oxygen from the alveoli and loses CO2 to inspired gas
Air enters the upper respiratory tract and passes through
- pharynx
- larynx
- trachea
- primary bronchi which branch into smaller bronchi
trachea and bronchi
semirigid tubes supported by cartilage
bronchioles
small collapsible airways with walls of smooth muscle
tidal volume
amount of air that moves into the lungs with each inspiration or the amount that moves out with each expiration during quiet breathing
inspiratory reserve volume
air inspired with a maximal inspiratory effort in excess of the TV
expiratory reserve volume
the volume expelled by an active expiratory effort after passive expiration
residual volume
air left in the lungs after a maximal expiratory rate
total lung capacity
comprised of residual volume, expiratory reserve volume, tidal volume, inspiratory reserve volume
successful external respiration
ventilate, perfuse alveolus, allow adequate diffusion of respiratory gases, accomodate several fold increases in demand for oxygen uptake or CO2 elimination imposed by metabolic needs or acid-base disturbances
asthma - 2 components
chronic inflammatory condition by dysregulation of:
- smooth muscle tone in the airways
- immune function in the airways
which airways will be most compromised - why
narrow most compromised - why????
main characteristics of asthma
- smooth muscle hyper responsiveness
- airway inflammation
- symptomatic bronchoconstriction
hyperresponsiveness
propensity for the airways of asthmatic patients to constrict in response to stimuli: allergens, environmental irritants, exercise, cold air and infections
hypersensitivity
hypersensitivity is normal response to abnormal low levels of stimuli
hyperreactivity
exaggerated response to normal levels of stimuli
T lymphocytes
crucial roll in controlling the immune response, major source of cytokines
read and recognize the antigens to coordinate an immune response
Th` switches off Th2
Th1 response
cellular immune response - does not involve antibodies
Th2 response
humoral immune response - involves antibody production by B-cells - exaggerated response in asthma
IL-4
induces B cells to produce exaggerated amounts of IgE antibodies against the allergen - Th2
IgE
IgE antibodies bind to IgE receptors on the surface of mast cells in the airways, upon re-exposure to the allergen and binding to the IgE/IgE recepter complex of mast cells: mast cell degranulation triggers an allergic reaction
omalizumab
monoclonal antibody directed against IgE and is the first biologic therapy to treat asthma - binds to circulating IgE to decrease the cell-bound IgE, decreases the expression of high affinity receptors. mast cell degranulation will decrease and antigen to receptor will decrease IgE and decrease receptor expression, dec asthma symptoms, allergic inflammation, and exacerbations - normal people have IgG so they do not get this response! Controller!
activated mast cells degranulate and release
histamine, leukotrienes, and proteases/proteoglycans
histamine
promotes capillary leakage leading to airway edema
leukotrienes
establish a delayed yet potent inflammatory effect
- induce bronchoconstriction (SM contraction)
- cause mucus hypersecretion
- cause capillary leakage worsening airway edema
- recruit inflammatory cells (esinophils)
proteases/proteoglycans
induce chronic changes in airway remodeling
hyperplasia (enlargement) of airway smooth muscle cells/mucus producing cells
fibrosis in collagen deposition
causes irreversible narrowing of the airways
montelukast
potent and selective antagonist of leukotriene D4 by blocking the physiologic actions of the leukotriene at its receptor (plasma exudation, mucus secretion, bronchoconstriction, and eosinophil recruitment would all be inhibited)
IL-13
response to Th2. causes goblet cells hyperplasia (mucus producing in airways) increased mucus production
causes the smooth muscle hyperplasia and/or hypertrophy, enhances smooth muscle contractility, airway remodeling: fibrosis, and stimulates IgE
IL-5
recruits eosinophils and promotes eosinophil proliferation, release from bone marrow and survival
mepolizumab
monoclonal antibody that targets IL-5. blocks IL-5 from binding to the receptor on the eosinophil surface. all events of creating and recruiting eosinophils will be inhibited
how to describe air flow and air resistance in asthmatics
air flow - reduced
airway resistance - increased
factors contributing to reduced airflow
- bronchoconstriction
- airway edema
- vascular congestion
- mucus production
asthma is an obstructive or restrictive lung disease
obstructive
FEV1 in asthma
FEV1 is forced expiratory volume in the first minute - it is reduced
FVC in asthm
reduced, it is the forced vital capacity
FEV1/FVC
reduced
acute asthma you will expect
air to be trapped in the lung
increased residual volume
hyperinflation from air trapped in the lungs
alveoli distal to the obstructed airways are (under/over) ventilated leading to mild arterial hypoxemia
under ventilated - supplementation with oxygen can correct hypoxemia
atopy
means allergy- strongest genetic risk factor- genetic predisposition to develop specific IgE antibodies directed against common environmental allergens
hygiene hypothesis
exposure to infections results in a shift towards a predominant protective Th1 immune response. so infections may increase the risk for asthma. infections are however are an important trigger of acute attacks in asthmatic patients
asthma risk factors
allergens/occupational exposure
obesity increases asthma risk
relievers
alleviate smooth muscle bronchoconstriction
controllers (preventers)
reduce airway inflammation, pathophysiologic basis for asthma, reduce acute attacks - anti-inflammatory agents
relievers
alleviate smooth muscle bronchoconstriction
albuterol
sympathetic activation - induces broncho dilation by acting on smooth muscle cells - reliever
B2 - agonists
B2 agonists activate B2 adrenergic receptors which are widely expressed in the airways. B2 receptor activation results in increased intracellular cyclic adenosine monophosphate, which relaxes smooth muscle cells and inhibits inflammatory cells - mast cells
anticholinergic agents
parasympathetic cholinergic activation acts on the muscurinic receptors in the airway smooth muscle that are activated by acetylcholine. acting as an agonist causes
side effects of anticholinergic
dry mouth, increased heart rate, urinary retention
why is it important to add a controller medication and not just treat the acute event
airway remodeling
COPD
chronic and progressive inflammatory lung disease in response to noxious particles or gases, preventable and treatable lung disorder. not fully reversible
cigarette smoking affects COPD
components of tobacco activate inflammatory cells - produce and release inflammatory mediators characteristic of COPD
important component in COPD
chronic bronchitis
emphysema
small airway disease: small bronchioles are narrowed - bronchoconstriction
chronic bronchitis
- long-term condition, inflammation of the bronchial tubes - large airway disease
- inflammatory condition with chronic or recurrent mucus secretion into the bronchial tree
chronic cough and sputum
cough present for at least 3 months of the year for 2 consecutive years in a patient whom has chronic cough that’s excluded
emphysema
abnormal enlargement of the airspaces distal to the terminal bronchioles with destruction of their walls - destruction of lung parenchyma
COPD targets which structures
primary/secondary bronchi, bronchioles, alveoli
underlying problem in COPD
exposure to noxious particles that sustain inflammatory response - inflammation targets the large and small airways, pulmonary vasculature and lung parenchyma result in chronic airflow limitation -
airflow limitation in COPD from
small airway obstruction and emphysema
inflammatory response in COPD
release elastolytic and proteinases that damage the extracellular matrix of the lung - structural cell death (endothelial and epithelial cells) causes the release of free radicals
extracellular matrix
tissue-specific macromolecular structure that provides physical support to tissues and essential for normal organ function
ineffective repair of structural damage results in
emphysema
major inflammatory cells in COPD
neutrophils
major inflammatory cells in asthma
mast cells, eosinophils
inflammatory mediators
leukotriene B4, interleukin 8 and tumor necrosis factor alpha
inflammatory mediators in asthma
leukotriene D4, IL-4,5,13
why wold montelukast be a bad option for COPD
potent and selective antagonist to leukotriene D4 not leukotriene B4!!
inflammation in large airways or bronchitis cause cough and sputum associated to
mucus gland enlargement, goblet hyperplasia (mucus producing cells), cigarette smoke paralyzes the cilia that sweep the mucus and debris out of the airways. as a consequence, patient may be at an increased risk for developing respiratory infection
metaplasia
bronchi undergo squamous metaplasia - replacement of one differentiated somatic cell type with another in the same tissue. benign non-cancerous change of surface lining cells (epithelium) to squamous morphology - thin flat cells look like fish scales and found in the tissue that forms the surface of the skin - lesions may progress to dysplasia and then to squamous cell carcinoma
neutrophil infiltration
purulent (discharge or pus) sputum
goblet cell metaplasia and in correlation with mucus
cells replace surfactant producing Clara cells in the respiratory bronchioles: mucus production will increase - reduced surfactant will increase surface tension at the air-tissue interface predisposing to airway collapse
role of surfactant
- decrease surface tension of fluid lining the alveoli reducing the likelihood that the lung will collapse
- increase the compliance of the normal lung so that less work is expended for breathing
- surfactant keeps the alveoli dry. high surface tension sucks fluid from alveolar walls with decreased surface tension provided by the surfactant - alveolar space is maintained in a relatively dry state - alveoli are covered with a thin fluid layer rather than filling up with fluid
structures compromised in COPD
- thickening of vessels bc hypoxia which inc pulmonary pressure
- endothelium becomes dysfunctional
- severe COPD: secondary pulmonary hypertension causing right sided failure
COPD host factors
- genetic predisposition
- airway hyperresonsiveness: condition associated to asthma
- impaired lung growth associated to low birth weight, prematurity at birth or childhood illness. prevent maximal lung growth
COPD environmental factors
particle inhalation that results in inflammation and cell injury, environmental tobacco smoke, occupational dust and chemicals, air pollution
genetic predisposition to COPD
hereditary deficiency of Alpha antitrypsin (AAT) -
AAT protects cells from destruction by elastase as elastase destroys fibers that allows the lungs to inflate and deflate - why pts have emphysema - develop COPD at an early age if they have this genetic disposition
inc/dec of forced expiratory flow rate, residual volume, residual volume/total lung capacity, FEV/FVC, FEV
dec forced expiratory flow
inc in residual volume (can result in barrel chest)
inc in residual volume/ total lung capacity ratio
dec in FEV and FEV/FVC ratio
ventilation in COPD
nonuniform distribution of ventilation
ventilation-perfusion mismatching also occur
lung hyperinflation
positive abdominal pressure during inspiration not applied as effectively to the chest wall. flat diaphragm has harder time doing normal pressure. cage is distended beyond normal resting volume. tidal breathing the inspiratory muscles must overcome the resistance of the thoracic cage to inflate - impairment of inspiration
nonuniform distribution of ventilation in COPD - why
parenchymal compartments have different rates of ventilation due to regional differences in compliance and airway resistance as a consequence of airway remodeling and parenchyma destruction
why does ventilation perfusion mismatching occur
low in partial pressure of oxygen in arterial blood. supplementation with oxygen is effective
exacerbation in COPD
exacerbation of the inflammatory response, worsening of the lung, hyperinflation contributing to worsening dyspnea and poor gas exchange - leads to hypoxia and hypercapnia, respiratory acidosis and respiratory failure - can be corrected with oxygen
COPD immunological complicatons
increased risk for respiratory infections
COPD cardiovascular infections
pulmonary hypertension and heart failure
COPD cancer
lung cancer
COPD bronchodilators to improve symptoms
beta agonists, cholinergic activity
What needs to be controlled in COPD and how
inflammation - control by inhaled/oral glucocorticoids
pulmonary arterial hypertension (PAH) definition
group 1 pulmonary hypertension, progressive disorder, elevation in arterial pressure and pulmonary vascular resistance, may progress to right heart dysfunction and failure. vascular remodeling
PAH etiology
- idiopathic (no known cause)
- familial: hereditary
- connective tissue disease: scleroderma and RA
- congenital heart disease
- HIV can play a role in developing PAH
portal hypertension
increased CO and reduced systemic vascular resistance leading to pulmonary arterial pressure. increased levels of circulating vasoconstrictor substances: endothelin 1
anorexigens
appetite suppressent. increased serotonin which acted as a growth factor for pulmonary arterial smooth muscle
endothelial dysfunction
dysfunctional endothelium alters vasodialator/vasoconstriction balance. abnormal proliferation of the smooth muscle cells (normal endo inhibits this). the earliest pathological features of vascular remodeling.
procoagulant state
reduced lumen favor in situ thrombosis. lung vascular continues with abnormal proliferation and differentiation of fibroblasts and increased extracellular matrix deposition and chronic inflammatory events in the adventitia
proliferation of smooth muscle cells leads to
medial hypertrophy in pulmonary muscular arteries: muscularization and advanced leads to intimal fibrosis
blocking of lumen from
disorganized proliferation of apoptosis-resistant endothelial cells, smooth muscle cells, fibroblasts, and macrophages lead to formation of a plexiform lesion: blocks lumen
PAH molecular mediators
prostacyclin (PGI2), thromboxane, endothelin-1, nitric oxide, 5-HT and coagulation factors
PGI2
vasodilatory and anti proliferative substance produced by the endothelial cells and the synthesis of PGI2 and its circulating levels are decreased in PAH
thromboxane
vasodialator, increased in PAH
ET-1
produced in the edothelium and possesses potent vasoconstrictor and mitogenic effects ( inc mitosis and cell proliferation) levels are increased and clearance is reduced in PAH
NO
produced in the endothelium via NO synthase and leads to vasodialation through calcium channel inhibition - leads to vasoconstriction and cell proliferation when no NO in PAH
NO
produced in the endothelium via NO synthase and leads to vasodilation through calcium channel inhibition - leads to vasoconstriction and cell proliferation when no NO in PAH
5-HT
elevated in PAH and vasoconstriction mediated via the increased expression of the 5-HT receptor seen in PAH
PAH coagulation factors
increased von willebrand factor
increased plasminogen activator inhibitor-1
reduced levels of tissue plasminogen activator
increased levels of 5-HT
increased thromboxane: vasoconstrictor and stimulus for platelet aggregation
signs and symptoms of PAH
dyspnea, fatigue, weakness, chest pain, presyncope/syncope, lower extremity edema, abdominal bloating/distension
pharmacologic target
supplementing endogenous vasodilators
inhibiting endogenous vasoconstrictors
reducing endothelial platelet interaction and limiting thrombosis
for efficient gas exchange
very high flow of blood at a very low pressure to limit alveolar injury and pulmonary edema - the right ventricle is designed to accept a large blood volume (preload) and pump blood against a low resistance (after load)
in PAH Right ventricle
RV will need more strength and more muscle to push through the pulmonary artery to a point where the right heart starts to dilate and fail as it is unable to meet the increased demands of the after load (resistance). PAH has a progressive increase in after load or PVR to a point where the right heart starts to dilate and fail. as it is unable to meet the increased demand of after load.
know the general anatomy smooth muscle, nerve, specialized cells in GI
enteric NS or enteric plexus - regulates movement and secretions
- serosa- connective tissue layer, peritoneum
- muscularis- circular muscle layer, longitudinal muscle layer
- submucosa
- mucosa- mucos epithelium, lamina propria, muscularis mucosa
specialized cells: digestive enzymes, mucous, acid, HCO3-, endocrine products
sympathetic (post gang)
parasymp (pregang)
name the 4 main saliva functions
- soften / moisten food: lubricates foot to facilitate swallowing
- taste: dissolves food so we can taste it
- defense: from pathogens, cell damage, self-digestion (IgA prevents infection, lysozyme prevents bacterial growth)
- digestion of starch and some fat: digestion of carbs by amylase and fats by lipase
describe the role of the autonomic NS in the regulation of saliva secretion
salivary glands regulated by PNS. release of Ach to M3 inc saliva production
describe the nervous system control of swallowing and the primary type of motility found in the esophagus
- voluntary phase of the skeletal muscle controlled by somatic motor NS
- involuntary phase controlled by smooth muscle innervated by the ANS. food entering and exiting esophagus controlled by two sphincter, one on top esophagus and upper esophageal sphincter and one at the bottom, the lower esophageal sphincter (barrier between stomach and esophagus)
describe the functions of the stomach
- food storage - gastric emptying rate controlled by pyrolic valve
- digestion- mechanical and chemical mixing of food to produce chyme
- protection: kills pathogens, denatures proteins
little absorption of nutrients but asprin and alcohol can both be absorbed
describe the function of all products secreted by gastric pits
mucus, acid, pepsin, endocrine products
gastrin
secreted: stomach,
acts in: ECL and parietal cells, stimulates gastric acid secretion and mucosal growth, stimulus of release: peptide and AA, neural reflexes
inhibited by somatostatin
CCK
secreted: intestine, produced by ENS neurons and endocrine cells of the duodenum and jejunum
acts in: gallbladder, pancreas, and stomach, stimulates gallbladder contraction and decreases motility, stimulates pancreatic secretion and inhibits gastric acid secretion, fatty acid and some amino acids are stimulus
secretin
secreted: intestine acts in: pancreas, stomach inhibits gastric emptying and motility stimulates hco3- secretion from pancreas/ inhibits acid secretion from parietal cells stimulus: acid in small intestine
motilin
secreted: intestine, endocrine cells
acts: gastric / intestinal smooth muscle
stimulates migrating motor complex
fasting; periodic release every 1.5 hours inhibited by eating
GIP “incretin”
secreted: intestine
acts: beta cells of pancreas
stimulates insluin release and inhibits acid secretion
inhibits gastric emptying
stimulus: glucose, fatty acids, AA in small intestines
GLP-1 “incretin”
secreted: intestine
acts: endocrine pancreas
motility: inhibits gastric emptying and inhibits food intake
stimulates insulin synthesis and release, inhibits glucagon release
stimulus: meal of fats / carbs in the lumen
