RESPIRATORY SYSTEM ANATOMICAL DEAD SPACE (DYNAMIC) key constant: airway resistance ...

key pressure: alveolar pressure key parameter: air flow key pathology: obstructive pulmonary disease (increases resistance) *ventilation around 30% of total *final conducting airway 150 mL in inspiration *stale alveolar 150 mL in expiration *measured by Fowler's N2-washout nares, nasal cavities - innervated by facial nerve - cell bodies in facial motor nucleus - turbinates increase turbulence - vibrissae filter out ~15um particles - where impaction and sedimentation of 2-10 um particles occur - process (warm, filter, moisturize) air

pharynx-larynx 0.6 cm H20/(L/s) - great resistance - innervated by CN IX and X - cell bodies in nucleus ambiguus (intermediate VRG) and DRG trachea 0.6 cm H20/(L/s)- combined with airways >2 mm - truly turbulent airflow - zeroth generation - lumen remains patent because of cartilage rings - low compliance - tend to collapse during expiration bronchi 0.6 cm H20/(L/s)- combined resistance with trachea and bronchioles greater than 2mm in diameter - first generation to tenth generation - M3 muscarinic receptoractivation on smooth muscle = constriction... +acetylcholine from parasympathetic vagus +leukotrienes LTC4 and LTD4 +vagal reflex constriction due to irritants - B2 adrenergic activation on smooth muscle = dilatation... +norepinephrine from sympathetic nerves ++epinephrine (blood humoral factor) from adrenal medulla high lung volume - transitional airflow - faster airflow than the trachea and the bronchi farther than gen 4 - static (no airflow): TM = +5 cm H2O

- dynamic inspiration: TM = +16 cm H2O - dynamic expiration: TM = -6 cm H2O bronchioles 0.3 cm H2O/(L/s)- resistance in bronchioles <2mm in diameter - eleventh to nineteenth generations - first sixteen are terminal, conducting... air moves by convection - slower airflow than in trachea due to large aggregate cross- sectional area - last three are respiratory... air moves by diffusion - constriction: histamine - dilatation: high lung volume - static: TM = +5 cm H2O - dynamic inspiration: TM = +12 to +8 cm H2O - dynamic expiration: TM = -2 to +2 cm H2O - COPD decreases their radius

ALVEOLAR SPACES (STATIC) key constant: static compliance key pressure: transpulmonary pressure key parameter: lung volume key pathology: restrictive pulmonary disease (lowers compliance) *includes respiratory bronchioles alveolar ducts, alveolar sacs, alveoli - twentieth to twenty-second generations (alveolar ducts) and twenty-third generation (alveolar sacs) - air moves by diffusion - almost no airflow - at maximal expiratory effort... at 5L, airflow is effort independent at low lung volumes (3 L), airflow is effort independent because of the lungs' tendency to collapse - static: TP = +5 cm H2O, PA = 0 cm H2O - dynamic inspiration: TP = +5 cm H2O, PA = -15 cm H2O - dynamic expiration: TP = + 5 cm H2O, PA = +15 cm H2O - macrophages remove particles; particles travel in mucus up and into pharynx; ~<0.5 um aerosolized and expelled during expiration or coughing - intrinsic properties: elastic recoil (tendency to deflate) and compliance (tendency to inflate) - causes of elastic recoil... cellular and interstitial component surface tension of water within the alveoli - surfactant decreases surface tension of alveolar fluid, decreasing elastic recoil, thus preventing lung from overly deflating - E = 1/C - C = 0.2 L/cm H2O - right lung is 55% of total lung mass - total lung capacity: volume after maximal inspiration, plus functional residual capacity volume (5 800 mL) - vital capacity: maximal volume inspired plus maximal volume expired (4 600 mL) - forced expiratory volume in 1 s (80% of vital capacity, 3680 mL) - functional residual capacity: amount left in the lungs after expiration (3 300 mL)

- tidal volume: normal amount expired and inspired (500 mL) - inspiratory reserve volume: maximally inhaled volume without tidal volume (3000 mL) - expiratory reserve volume: maximally exhaled volume without tidal volume (1 100 mL) - residual volume: amount always left in the lung after maximal expiration (1 200 mL) - inspiratory capacity: maximally inhaled volume (3 500 mL) - respiratory frequency: 12 breaths per minute... increases decrease amount of air moving into and out of the lung, lowering tidal volume (increases time constant) - time constant: 0.2s; amount of time for lung volume to reach 63% of total - VA (alveolar ventilation) = 4.2 L/min - VL (lung ventilation) = 6 L/min - VD (dead space ventilation) = (6-4.2) L/min = 1.8 L/min physiological dead space = anatomic dead space - alveolar dead space - alveolar dead space: pathologic condition where air does not flow in alveoli -VA=0.863 (VCO2/PCO2), alveolar ventilation equation - 200mL CO2 expired (PCO2=40 mmHg) - 250mL O2 inspired (PAO2=109 mmHg) - PAO2= PIO2-PACO2 when respiratory quotient is 1 - gravity and postural factors affecting regional areas... at apex: alveoli are overinflated, but are less compliant (lower ch. in VL) at base: alveoli are underinflated, but are more compliant (larger ch. in VL) PULMONARY VESSELS - low pressure - low resistance - high compliance - left ventricular reservoir (contain 500mL of blood) that maintains cardiac output for ~2 beats - trap emboli from mixed- venous systemic blood before they lodge in the systemic circulation - biochemical reactions of endothelial cells... convert angiotensin I into angiotensin II remove PGE1 PGE2 PGF2a leukotrienes serotonin bradykinin angiotensin I maintain PGA1 PGA2 PGI2 histamine epinephrine dopamine angiotensin II arginine vasopressin gastrin oxytocin - important in acid-base physiology - blood spends 0.75s in capillaries

- where perfusion also occurs blood PERFUSION-limited gases O2 98% as oxyhemoglobin 2% as dissolved O2 CO2 90% bicarbonate 5% dissolved CO2 5% carbaminohemoglobin carbonic acid carbonate pulmonary arteries - PAO2 = 40 mmHg (15.3 ml/dL blood) - PACO2 = 46 mmHg (52 mL/dL blood) pulmonary capillaries ~280 B segments; 1000 per alveolus = 100m2 area for gas diffusion - pulsatile blood flow - can be: open and conducting blood (distends at high Pa) open and not conducting blood (conducts at high Pa) closed (recruited at high Pa) - take up 4.7 mL O2/dL blood - release 4 mL CO2/dL blood 11% in blood plasma 6% dissolved 5% bicarbonate ins. plasma protein carbamino 89% in RBC 64% bicarbonate 21% carbaminohemoglobin 4% dissolved in cytoplasm vascular resistance... decreases (vessel dilates) with high PO2 low PCO2 high pH histamine H2 agonists PGI2 or prostacyclin PGE1 B-adrenergic agonists bradykinin theophylline acetylcholine NO increases (vessel constricts) with opposite blood parameters histamine H1 agonists thromboxane A2 PGF2a

PGE2 a-adrenergic agonists serotonin angiotensin 2 pulmonary veins - PAO2 = 100 mmHg (20.0 mL/dL blood) - PACO2 = 40 mmHg (48 mL/dL blood) - regional perfusion differences due to gravity and posture (left atrium reference point for ch. in P)... ZONE 1 - abnormal; arise in decrease in Ppa (as in hemorrhage), increase in PA (as in positive-pressure ventilation - PA>Ppa>Ppv, -TM crushes capillary and reduces blood flow ZONE 2 - from apex to midlung - Ppa>PA>Ppv, increase in hydrostatic pressure toward base reduces crushing force, and recruits vessels *high ventilation ZONE 3 - middle to lower lung - Ppa>Ppv>PA, +TM causes distention - zone of maximal perfusion ZONE 4 - extreme base of lung - Ppa>Ppv>PA, resistance of extra-alveolar vessels increases, reducing perfusion *ventilation is lowest here *Pressure rises by 1 cm H20 for every 1 cm descent alveolar vessels - TM = P in lumen - P in alveoli - stretching alveolar walls (increasing VL) decreases diameter, increasing vessel resistance extra-alveolar vessels - not surrounded by alveoli - increasing IP (as in expiration) decreases diameter, increasing vessel resistance - VA/Q, ventilation perfusion ratio... high at apex alveolar gas pressures approximate air gas pressures pathological: alveolar dead space ventilation (air enters the alveolus, but no blood runs through the alveolar capillaries) as in pulmonary embolism low at base alveolar gas pressures approximate mixed venous-blood, which is 0 pathological: shunt (no air enters alveolus but blood passes through alveolar capillaries) as in atelectasis and airway obstruction normal: thebesian veins, bronchial arteries BLOOD PARAMETERS pH BUFFERS buffering power (B) depends on: total conc. of buffer pair pH of solution open or close system arterial HCO3- = 24mM EXTRACELLULAR non-HCO3- B = 25mM/pH

HCO3- B arterial = 2.6 mM/pH HCO3- B open (lung) = 55 mM/pH w/o non-HCO3- buffers: doubling PCO2 decreases pH by 0.3 doubling bicarbonate increases pH by 0.3 Davenport diagram combines HCO3-buffering with non-HCO3- buffering position on disturbance as metabolic or respiratory w/ non-HCO3- buffers: increase in HCO3- as PCO2 is increased Perfect compensation of respiratory acidosis OR metabolic ALKALOSIS = isohydric hypercapnia... same pH at higher PCO2 Perfect compensation of respiratory alkalosis OR metabolic ACIDOSIS = isohydric hypocapnia... same pH at lower PO2

diagram defines

INTRACELLULAR carbonic anhydrase converts CO2 and H20 into H2CO3, which dissociates into H+ and HCO3homeostatic mechanisms Na-H exchanger (acid extruder) low pH activation high pH inactivation Cl- -HCO3- exchanger (acid loader) low pH inactivation high pH activation increases the formation of HCO3- as HCO3- is transported out of cells (Hamburger shift) Na/HCO3- cotransporter K+ depolarization triggers activation, increasing pH K+ inward transporters low pH inactivation leads to extracellular hyperkalemia intracellular pH changes only 20% to 60% of the change in extracellular pH PO2 arterial blood Hb is 97.5% saturated mixed-venous blood Hb is 75% saturated blood is saturated 1/3 the length of the pulmonary capillary release from hemoglobin is due to higher temperature higher CO2 conc. (Bohr effect) 1 CO2 replaces 1 O2 lower pH (higher H+) 2 H+ replace 4 O2 2,3-DPG 1 2,3-DPG replaces 4 O2 *first three characteristic of metabolically active tissues PCO2 presumably saturates blood 1/3 the way of the capillary release from hemoglobin is due to higher O2 conc. (Haldane effect) DIFFUSION and PERFUSION

Fick's principle Net flow of gas = diffusing capacity for the lung (DL) x (P1-P2) DL factors gas properties: solubility MW barrier properties: area thickness DL is the reciprocal of 1/Dm + 1/theta Vc, where Dm represents the layers that the gas must pass through, which amount to 12 in the lung (air,water,pneumocyte membrane,cytoplasm,memb,interstitial matrix, endothelial memb, cyt,memb,blood plasma,RBCmemb,cyt) and where theta Vc represents the binding to hemoglobin (5% as large as Dm) CO diffusion limitation flux through the alveolar-blood barrier is slow Hb traps CO (200 to 300 timesfaster than O2) CO in the blood can never reach equilibrium with alveolar CO even though blood flow is diffusion limitation is overcome by increasing pulmonary capillary blood volume CO diffusing capacity is used as estimate of diffusing capacity for thelung

increased

N2O perfusion limitation is not diffusion-limited because it reaches alveolar concentrations at only 10% of the capillary length is not diffusion-limited because it does not bind to hemoglobin is perfusion limited because flux stops at equilibrium perfusion limitation is overcome when blood flow is increased

Control of ventilation Eupnea - regular rhythmic breathing

Apneusis - prolonged inspiratory effort separated by brief expirations - generated by diffuse neurons in caudal pons - pneumotaxic nucleus parabrachialis medialis and Kolliker-Fuse nucleus in rostral pons prevent apneusis - increasing temperature reduces apneusis Pneumotaxis - reduction of overinhalation, coordination of respiration

Nucleus Tractus Solitarii (NTS) - receive all visceral afferent input from the thorax and abdomen - respiratory portion located ventrolateral to tractus solitarius in medulla Tractus solitarius - lies below the floor of the caudal end of the fourth ventricle Reticular Activating System - provide tonic stimulation Respiratory-Related Neurons - activity patterns correlate with breathing - in pons and medulla - inspiratory and expiratory subtypes based on

*how firing correlates to the respiratory cycle some fire during inspiration only others fire during expration only *responses to afferent inputs - some may play indirect role by providing tonic drive - firing patterns depend on: ion channels (intrinsic membrane properties) K+ transient A-type current -fires action potentials after a delay -mainly responsible for late firing during inspiration - hyperpolarization REMOVES INactivation (K+ moves out) and depolarization further activates current hyperpolarization), thus inhibiting action potential - further depolarization causes channel closure, allowing pacemaker current - in NTS (DRG) and pre-Botzinger complex - "beating" (one-at-a-time) pacemakers and "bursting" - TRH from axon of medullary raphe entering NTS stimulates - contribute respiratory rhythm or augment respiratory output - not necessary for rhythmic output synaptic input - rhythm depends not on individual neuronal properties but (EPSPs or IPSPs) - network model

(transiently; K+ moves out, causing action potential to occur

(repetitive spikes) pacemakers "bursting" pacemakers within other sites

on their synaptic connections

Dorsal Respiratory Group - respiratory NTS and immediately adjacent neurons in the dorsal medulla - integrate SENSORY information from mechanoreceptors and chemoreceptors of *the lung and distal conducting (lower) portion of the lung through CN X *upper conducting passages through CN IX - contains: *interneurons *premotor neurons to spinal intercostals and phrenic AFFERENTS Peripheral Chemoreceptors more rapid response than central counterpart acutely responsible for Kussmaul breathing Aortic bodies alongside underside of aortic arch differ from carotid bodies in sensitivity and effects to ventilation presumably have the same types of cells as the carotid bodies transmit signals through CN X Carotid bodies on bifurcation of common carotid artery ~ 2 mg receive 40-fold higher blood flow than in the brain 2- to 3-fold higher metabolic rate than the brain functional chemoreceptors are type I cells (glomus neurons) : innervated by preganglionic cells

contain a variety of voltage-gated ion channels generate action potentials when depolarized contain neurotransmitter vesicles containing dopamine, acetylcholine, norepinephrine, and substance P innervated by both sympathetic and parasympathetic ANS synapse with afferent axons of CN IX sympathetic stimulation of adjacent blood vessels constricts vessels and fools glomus cells into detection of hypoxia increase firing rate due to inhibition of (hyper)polarizing BK K+ channels under decreased PO2 (lowers probability of open K+ channels) deoxygenated heme-containing protein rise in cAMP, inhibiing cAMP-sensitive currents inhibits glutathione oxidase in mitochondria reduced glutathion directly inhibits channels increased PCO2 CO2 enters cells and generates H+ which displace Ca2+ from the binding sites of BK K+ channels, inhibiting high K+ conductance decreased pH (extracellular) slowly triggers intracellular acidosis by stimulating acid loaders and inhibiting acid extruders decreased BK K+ conductance depolarizes the cell, triggering the opening of voltage-gated Ca2+ channels, influx of Ca2+, and subsequent release of transmitter (dopamine) to CN IX axon more sensitive to hypoxia under hyperacidic conditions and glial components are type II cells (sustentacular cells) fenestrated capillaries Central Chemoreceptors account for 65% to 80% of response to respiratory acidosis In brain medulla near surface of ventrolateral medulla contain serotonergic neurons medullary raphe unusually pH-sensitive reciprocal inhibition stimulation: serotonin inhibition of inhibitory neurons: GABA lie close to basilar artery nucleus ambiguus NTS locus coerulus hypothalamus stimulation caused by detection of local (extracellular or intracellular) increased PCO2 (respiratory acidosis) more effective in triggering than HCO3- and pH; higher H+) because of bloodbrain barrier (BBB) CO2 easily diffuses through BBB but HCO3- and H+ do not ventilation more rapid under respiratory acidosis than in metabolic acidosis pH changes in brain blood during metabolic acidosis: only 10% to 35% as acidosis acidosis in BECF metabolic acidosis (lower vice versa

effective as in respiratory

Slowly Adapting Pulmonary Stretch Receptors (PSRs) firing rate decays slowly over time involved in Hering-Breuer reflex prevents overinflation by decreasing phrenic nerve output maintain constant alveolar ventilation and tidal volume by increasing Rapidly Adapting Stretch Receptors (Irritant) very sensitive serotonin, histamine, bradykinin, prostaglandins, cigarette smoke, detect chemical irritants,congestion, inflammation rapidly increases firing rate, but rate decays by 80% within 1 s

respiratory frequency

ammonia, ether

Unmyelinated C-fiber Receptors (juxtacapillary or J receptors and airway receptors) favor deposition of foreign particles in upper tract mucus by: increasing bronchoconstriction inducing rapid, shallowing breathing increasing mucus secretion Ventral Respiratory Group - longer column of nuclei that lie midway ro the dorsal and ventral surfaces of the medulla - divided into rostral, intermediate, and caudal - include nucleus ambiguus (CN IX and CN X bodies), nucleus para-ambigualis, nucleus retroambigualis - receives sensory information indirectly from DRG - contains: *interneurons in rostral VRG (Botzinger complex) - drive expiratory activity of the caudal VRG *premotor neurons in intermediate VRG - to inspiratory motor neurons in spinal cord and medulla premotor neurons in caudal VRG - travel in spinal cord to synapse with motor neurons of accessory muscles of expiration *MOTOR neurons in intermediate VRG - axons leave as CN IX and CN X Central Pattern Generator - autonomic component that controls the rhythm of ventilation - runs regularly during quiet breathing or sleep - found in the medulla - modulated by the pons, higher CNS, sensory mechanisms (peripheral chemoreceptors and central chemoreceptors) - exact location is unknown

Models Restricted-Site - CPG lies in the pre-Botzinger complex of the VRG Distributed Oscillator - CPG changes in location with changes in condition - CPG in multiple areas; neurons with oscillatory behavior contribute to rhythmicity only under unusual conditions - CPG is only one for eupnea but other regions (unable to generate rhythmicity) can augment it Emergent Property - MANY neurons are necessary to create normal respiratory rhythm - CPG does not depend on an individual DRG or VRG region

Modification of Ventilation: Voluntary control overrides chemical drives, and vice versa Coordination with behaviors that require respiratory muscles

Cerebral cortex control: cortical axons to respiratory centers cortical premotor axons to respiratory muscles Coordination with behavior not related to ventilation distinct descending pathways from medullary premotor neurons pathway Modification by affective states along with descending pathways from the limbic system Respiratory Motor Behaviors Sigh (asgmented breath) - counteracts decreased alveolar ventilation and atelectasis - stimulates release of surfactant, opening collapsed alveoli - frequency increases with hypoxia and respiratory acidosis Yawn - minimizes atelectasis before and after sleep Cough (respiratory scratch) reflex - forced expiratory effort against a closed glottis, which opens suddenly and causes pressure to drop to extremely low values, collapsing the tracheal opening to 1/6 its normal size, leading to air velocities near 800 km/h (65% speed of sound) Sneeze - differs from cough because it is almost always preceded by deep inspiration - net effect is expulsion of foreign bodies from the pharynx and nasal mucose Reticulospinal tract lesions (Ondine's curse) - breathing only occurs autonomically during wakefulness Sleep - REM (and NREM) states lower sensitivity to PCO2 - highly regular breathin in NREM state; highly irregular breathing REM state - barbiturates depress respiratory drive and can halt ventilation during sleep - decreased airway tone Sleep Apnea - due to lack of central respiratory drive (central sleep apnea) collapse of airways (obstructive sleep apnea) - commonly associated with severe snoring, daytime somnolence, and obesity See More

behavioral changes, as well as