Respiratory System

• Provides O2
• Eliminates CO2
• Regulate blood’s hydrogen ion concentration (pH) along with kidneys
• Phonation
• Defends against microbes; mucus, cilia. Type II cells make surfactant which is also part of immune system.
• Influences arterial concentrations of chemical messengers by removing some from pulmonary capillary blood and producing and adding others to this blood. Converts Angiotensinogen to Angiotensin II (vasoconstrictor) to help regulate BP.
• Traps and dissolves blood clots arising from systemic veins.

• Respiratory muscles
• Lungs
• CNS centers in Medulla control respiration and integrate rhythmic patters which can be overridden voluntarily

Allows lungs to slide and has adhesion quality so lungs will expand with the chest wall.

• Nasal cavity to bronchioles
• 150mL dead space
• Cleans, warms, moistens air
• Distributes air to deeper parts of lung
• Dilation/constriction of smooth muscle determines air flow (R)Defense mucociliary transport system

• 3L
• Gas exchange between alveoli and capillary

• Angiotensinogen is an α-2-globulin that is produced constitutively and released into the circulation mainly by the liver.
• Plasma angiotensinogen levels are increased by plasma corticosteroid, estrogen, thyroid hormone, and angiotensin II levels.

Angiotensin I is formed by the action of renin on angiotensinogen. Renin is produced in the kidneys in response to both decreased intra-renal blood pressure at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa. If more Na+ is sensed, renin release is decreased. Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating angiotensin I. Angiotensin I appears to have no biological activity and exists solely as a precursor to angiotensin 2.

Angiotensin I is converted to angiotensin II through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE, or kinase), which is found predominantly in the capillaries of the lung. ACE is actually found all over the body, but has its highest density in the lung due to the high density of capillary beds there. Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrine hormone.

ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of angiotensin II production. Angiotensin II increases blood pressure by stimulating the Gq protein in vascular smooth muscle cells. ACE inhibitor drugs are major drugs against hypertension.

• Angiotensin II has a direct effect on the proximal tubules to increase Na+ reabsorption.
• It has a complex and variable effect on glomerular filtration and renal blood flow depending on the setting. Increases in systemic blood pressure will maintain renal perfusion pressure, however constriction of the afferent and efferent glomerular arterioles will tend to restrict renal blood flow. The effect on the efferent arteriolar resistance is, however, markedly greater, in part due to its smaller basal diameter; this tends to increase glomerular capillary hydrostatic pressure and maintain glomerular filtration rate. A number of other mechanisms can affect renal blood flow and GFR.
• High concentrations of Angiotensin II can constrict the glomerular mesangium reducing the area for glomerular filtration. Angiotensin II as a sensitizer to tubuloglomerular feedback preventing an excessive rise in GFR. Angiotensin II causes the local release of prostaglandins, which, in turn, antagonize renal vasoconstriction. The net effect of these competing mechanisms on glomerular filtration will vary with the physiological and pharmacological environment.

• Flat epithelial cells
• Gas exchange

• Produce surfactant which reduces surface tension, stabilizes the alveoli, and has defense function.
• Premature infants (<31 wks) cannot make surfactant and cannot expand lungs to breathe, Respiratory Distress Syndrome.
• Surfactant production is regulated by Cortisol.

Exchange of air between atmosphere and alveoli

• Inspiration when Patm > Palv
• Expiration when Patm < Palv
• Between breaths Patm = Palv so F = 0

• Ventilation Cycle = one inspiration and one expiration
• Normal approx. 10-18 breaths/min
• Tidal Volume approx. 0.5 L/breath
• Minute Ventilation (VE = TV x f)
• 0.5 L/breath x 10 breaths/min = 5 L/min
• Depth and rate can be changed by output from the respiratory centers in the medulla oblongata.
• During heavy exercise, air flow can increase 20-fold (with active expiration) but blood flow only 3-fold (limiting factor).

• Bulk Flow
• F = ΔP/R

Volume of air inhaled or exhaled in one breath during relaxed, quiet breathing. (approx 0.5 L but depends on body size)

Amount of air in excess of tidal inspiration that can be inhaled with maximum effort. (approx. 3L)

Amount of air in excess of tidal expiration that can be exhaled with maximum effort. (approx. 1.5 L)

Amount of air remaining in lungs after maximum expiration; keeps alveoli inflated between breaths and mixes with fresh air on next inspiration. Cannot measure with spirometer. (approx. 1 L)

• Amount of air that can be exhaled with maximum effort after maximum inspiration.
• VC = ERV + TV + IRV

• Maximum amount of air that can be inhaled after a normal tidal expiration.
• IC = TV + IRV

• Amount of air remaining in the lungs after a normal tidal expiration.
• FRC = RV + ERV

• Maximum amount of air the lungs can contain
• TLC = RV + VC

• 1. Varies with lung size.
• Compliance decreases at high lung volumes. [Lung compliance is less at apex of lung than at base. Why?] Alveoli are pulled more open at apex than at base due to gravity. Easier to fill bottom third of lung.
• 2. When compliance is abnormally low (“balloon”), the lung is stiff, inhalation is difficult but exhalation is easy. Smooth muscle and connective tissue do not stretch well and rebound back to their shape.
• 3. Increased compliance filling is easy, exhalation is difficult. [Natural aging increases compliance. Why?] Easier to fill balloon when it is almost empty than when it is nearly full.

• Patm = 760 mmHG is designated as = 0 mmHg
• Alveoli pressure = PA
• F = (PA – Patm)/R
• Transpulmonary Pressure is the difference between the pressure inside and outside the lung.
• (Ptp) = Palv – Pip
• Pip is always < Palv
• Ptp = elastic recoil when no air flow
• Ptp determines lung volume
• Ptp = PA – Pip
• Normally, PA = 0, Pip = -4, so Ptp = 0 – (-4) = 4
• At FRC, lung recoil = chest wall recoil
• Lung at FRC is at minimal size.
• When Pip = 0, lung will shrink and chest wall expands, no breathing, equilibrium.

When lung collapses, Ptp = 0 mmHg

• FE in normal lung: Pip > Pairway, equal pressures where airway has cartilage so there is no compression of airway.
• FE in obstructive lung disease: Pip > Pairway, unequal pressures where airway has no cartilage, greater pressure outside bronchiole than inside so it collapses, hear wheezing and crackles.

Maximal volume of air that a person can expire after a maximal inspiration.

• Individual takes a maximal inspiration and then exhales as fast as possible. Normal individuals expire approx. 80% of their VC in one second.
• Obstructive Lung Disease (asthma): FEV1/FVC < 80%, but they have normal FVC.
• Restrictive Lung Disease (fibrosis): FEV1/FVC = 80%, but they have reduced FVC.

• Myocardium: Positive Inotrope (increases strength of muscular contraction), Negative Chronotrope (decrease heart rate)
• Vasoconstriction of arteries to heart (coronary arteries)
• Venoconstriction of veins
• Decrease motility of smooth muscle in gastrointestinal tract

• Vasodilation of arteries
• Vasoconstriction of arteries to heart (coronary artery)
• Vasoconstriction of veins
• Decrease motility of smooth muscle in gastrointestinal tract
• Contraction of male genitalia during ejaculation

• Stimulate viscous, amylase-filled secretions from salivary glands
• Increase cardiac output:
• Increase heart rate in sinoatrial node (SA node) (chronotropic effect)
• Increase atrial cardiac muscle contractility. (inotropic effect)
• Increases contractility and automaticity of ventricular cardiac muscle.
• Increases conduction and automaticity of atrioventricular node (AV node)
• Renin release from juxtaglomerular cells.
• Lipolysis in adipose tissue.
• Receptor also present in cerebral cortex.

• Increase cardiac output (minor degree compared to β1).
• Increase heart rate in sinoatrial node (SA node) (chronotropic effect).
• Increase atrial cardiac muscle contractility. (inotropic effect).
• Increases contractility and automaticity of ventricular cardiac muscle.
• Dilate hepatic artery.
• Dilate arteries to skeletal muscle.
• Glycogenolysis and gluconeogenesis in liver.
• Glycogenolysis and lactate release in skeletal muscle.
• Contract sphincters of GI tract.
• Insulin secretion from pancreas.
• Thickened secretions from salivary glands.
• Inhibit histamine-release from mast cells.
• Increase protein content of secretions from lacrimal glands.
• Increase renin secretion from kidney.
• Receptor also present in cerebellum.
• Bronchiole dilation (targeted while treating asthma attacks)

• VE (minute ventilation) = TV – f (frequency breaths/min)
• VA (alveolar ventilation in mL/min) = (TV – VD) x f
• TV = tidal volume (mL/breath)
• VD = dead space (mL/breath) = 150mL

• Dalton’s Law: Sum of the partial pressures of gases = total pressure.
• PO2 of atm air = FiO2 x Patm = (0.21 x 760 mmHg) = 160 mmHg
• Inspired air is warmed and humidified.
• Water vapor pressure = 47 mmHg
• PO2 inspired air = 0.21 x (760 – 47) = 150 mmHg

• Alveolar gas pressures determine systemic arterial blood gas pressures (in mmHg).
• PO2:
• Arterial system = 100
• Venous system = 40
• Alveoli = 105
• Atm = 160
• PCO2:
• Arterial system = 40
• Venous system = 46
• Alveoli = 40
• Atm = 0.3

• Arterial O2 tension
• Measured in blood draw

• Arterial CO2 tension
• Measured in blood draw

• Alveolar O2 tension
• Determined by 3 factors:
• 1. PO2 of atmostpheric air (FiO2 x Patm – PH2O)
• 2. Alveolar ventilation rate (PaCO2), how much CO2 is being blown off.
• 3. Rate of tissue O2 consumption (RQ)

• Calculated by alveolar gas equation:
• PA02 = FiO2 x (Patm – PH2O) – PaCO2/RQ

• If breathing room air, then it simplifies to:
• PAO2 = 150 – 1.25 x PaCO2

• Large PaCO2 is not normal. Should be 40.
• PaCO2 sets the gradient for the whole system.

• Breathing air with low PO2 = decreases PAO2 = No change in PACO2.
• Increased alveolar ventilation and unchanged metabolism = increases PAO2 = decreases PACO2.
• Decreased alveolar ventilation and unchanged metabolism = decreases PAO2 = increases PACO2.
• Increased metabolism and unchanged alveolar ventilation = decreases PAO2 = increases PACO2.
• Decreased metabolism and unchanged alveolar ventilation = increases PAO2 = decreases PACO2.
• Proportional increases in metabolism and alveolar ventilation = unchanged PAO2 and PACO2.

• Hypoventilation: CO2 production > alveolar ventilation, increased PaCO2, PaCO2 > 40 is retaining CO2 and PaO2 falls below 100.
• Hyperventilation: CO2 production < alveolar ventilation, decreased PaCO2 falls below 40 and PaO2 > 100.

• Normal diffusion of O2 across pulmonary capillaries is always sufficient.
• Diffusion of O2 takes 0.3s and it takes 0.7s for blood to move through capillary.
• PAO2 determines the diffusion gradients throughout the cardiopulmonary system.

• O2 not very soluble in plasma
• 15 g Hb /100 mL blood

• Arterial blood is considered 100% saturated at PO2 = 60 mmHg and above.
• Venous blood has O2 saturation of 75% at 40 mmHg.
• O2-Hb binds cooperatively:
• Hb loads and unloads only one O2 at a time.
• After binding 1st O2, it gets easier to bind each subsequent O2.
• Fetal HbF is slightly different and can load and unload O2 and lower pressures.

• Left Shift:
• Increased affinity for O2, less easily unloaded.
• Decrease in DPG, low acidity (high pH), and low temperatures cause left shift.

• Right Shift:
• Decreased affinity for O2, more easily unloaded.
• Increase in DPG, high acidity (low pH), and high temperatures cause right shift.

• CO2 is very soluble in plasma and does not need carrier.
• Bicarbonate ion (HCO3-) = 60%
• Bound to Hb in RBC by carbaminoHb = 30%
• Dissolved in plasma PCO2 = 10%

• H2O = CO2 =c.a.= H2CO3 – HCO3- + H+
• c.a. = carbonic anhydrase, converts CO2 to H2CO3 which dissociates to HCO3- and H+
• H2CO3 is carbonic acid

• In tissues, O2-Hb becomes deoxy-Hb and binds newly generated H+ “buffering” the blood.
• Venous blood pH = 7.36 is slightly acidic
• Arterial blood pH = 7.4
• In alveoli, O2 binds to Hb releasing H+ which combines with bicarbonate to form H2O and CO2. This removes H+ and corrects arterial pH to 7.4

When ventilation falls and PaCO2 > 40 mmHg

When ventilation increases and PaCO2 < 40 mmHg

• Hering-Breuer Reflex
• Activated by large lung inflation, sending action potentials to inhibit activity of the medullary inspiratory neurons.

Very sensitive to inhibition by drugs such as barbiturates and morphine.

• Located in carotid bodies and aortic bodies.
• Carotid bodies monitor oxygen supply to the brain.
• Stimulated mainly by decrease in arterial PaO2 (hypoxia), increased PaCO2 (respiratory acidosis), and an increase in arterial H+ concentration (metabolic acidosis, low pH).

• Located in medulla oblongata.
• Respond to changes in the brain extracellular fluid.
• Stimulated by increased PCO2 via associated changes in H+ concentration in the brain’s extracellular fluid.

• Located in the capillary walls or the interstitium.
• Stimulated by an increase in lung interstitial pressure caused by edema in the interstitium.
• Increased pressure can be caused by pulmonary embolus, left ventricular heart failure, and strong exercise.
• Causes rapid breathing and dry cough and sensations of pressure in chest and dyspnea.

Hypoxic Hypoxia: PaO2 < 60

Anemic Hypoxia: decreased RBC or decreased Hb content

Ischemic Hypoxia: low blood flow to tissues

Histotoxic Hypoxia: poisoned cell metabolism

• Hypoventilation (low or shallow rate)
• Diffusion impairment (ex: pulmonary edema)
• Ventilation-perfusion inequality (V-Q mismatch): In normal lung, V/Q = 4L/min ÷ 5L/min = 0.8
• In normal lungs, gravity causes greater perfusion and greater ventilation of lower 1/3 than upper 1/3 of the lung. This lowers the PaO2 relative to the PAO2 called the A-a gradient.

• V/Q mismatch lowers PaO2
• If ventilation is low (ex: emphysema), PACO2 will be high, causing vasoconstriction. V/Q < 1
• If perfusion is low (ex: pulmonary embolism or fibrosis), PACO2 will be low, causing bronchiolar constriction. V/Q > 1
• High PCO2 in lung causes vasoconstriction. Everywhere else, high PCO2 causes vasodilation.

• PAO2 = 150 – (1.25 x PaCO2)
• PAO2 – PaO2 = A-a gradient
• Up to middle age, breathing ambient air normal A-a gradient ranges from 5-20mmHg. If it is increased, then there is a defect in gas transfer within the lungs. This is almost always due to V-Q mismatch.