I.  Introduction
 A.  Definition of respiration
  1.  Internal--metabolic processes carried out within the mitochondria
  2.  External--sequence of events resulting in an exchange of gases between the external environment and cells of the body
 B.  Overview of external respiration
  1.  Inspiration/expiration=ventilation
  2.  gas exchange between lungs and blood
  3.  Gas transport in blood
  4.  Exchange of gases between blood and tissues

II.  Anatomy of the pulmonary system
 A.  Alveoli
  1.  Clusters of thin-walled inflatable sacs at the ends of the airways
   -wall made of flattened Type 1 alveolar cells
  2.  Pulmonary capillaries
   -surround each alveolus
   -space between capillary and alveolus is 0.2 mm
  3.  Type II cells
   -secrete pulmonary surfactant
    -a phospholipoprotein that facilitates lung expansion
  4.  Macrophages
  5.  Pores of Kohn
   -pores allow airflow between adjacent alveoli (collateral ventilation)
   -especially important in diseases in which the airway is blocked

III.  Ventilation
 A.  Role of air pressures on air movement
  1.  Air moves down pressure gradients
  2.  Airflow into and out of lungs occurs as air flows down a pressure gradient between alveoli and atmosphere
  3.  Boyle’s Law
   -at constant temperature, the pressure of a gas is inversely related to the volume it occupies
   -therefore, if you increase the volume a gas is in, you decrease the air pressure
   -changing volumes of the chest cavity results in changes in intra-alveolar pressure and causes movement of air
 B.  Pressures involved in ventilation
  1.  Atmospheric (barometric)
   -pressure exerted by pressure of gases in atmosphere
   -this changes at varying altitudes
   -760 mm of mercury at sea level
  2.  Intra-alveolar pressure (aka pulmonary pressure)
  3.  Intrapleural pressure (does not equilibrate with any other air pressure as    air cannot normally flow between pleural sac and atmosphere or     lungs
   -normally slightly less than atmospheric pressure
  4.  Transmural pressure gradient
   -pressure gradient between alveoli and pleural sac
   -alveoli>pleural sac
   -walls of alveoli push out against pleural sac because of higher pressure within
   -helps keep air sacs inflated
  5.  Transthoracic pressure gradient
   -pressure on chest exceeds pressure iwthin cavity
   -partially responsible for pulmonary volume following volume of chest cavity since lungs don’t directly attach to wall of chest

 C.  Air Flow
  1.  Factors involved:
   a.  Pressure gradient (delta P)
   b.  Resistance to flow
    -determined by radius of airway
   c.  Flow=delta P/R
  2.  Ventilation cycle (quiet breathing)
   a.  Drop pressure in lungs by expanding thoracic cavity
    -phrenic nerve stimulates diaphragm to contract, moving it downward
    -external intercostals move ribs up and out
   b.  Lungs expand
   c.  Creation of pressure gradient allow movement of air into lungs
   d.  Relaxation of inspiratory muscles
    -thoracic cavity returns to initial size
    -lungs recoil (due to elastic properties)
   e.  Elastic recoil drops pressure in lungs below atmospheric pressure, creating a pressure gradient and allowing expiration of air
  3.  Work of ventilation
   a.  Inspiration-always requires energy
    -more energy required in obstructive diseases and accessory muscles called into action
   b.  Expiration-requires energy only during a forced expiration, otherwise simple relaxation of inspiratory muscles is sufficient for expiration in quiet breathing.
   c.  Forced expiration- requires energy and involves use of abdominal muscles and internal intercostals.

  4.  Factors Affecting Airway Radius
   a.  Autonomic nervous system
    -parasympathetic-bronchiolar smooth muscle constricts
    -sympathetic-bronchodilation
   b.  Local changes in CO2
    -increased CO2 causes bronchodilation (to  “blow off” more CO2 and vice versa
   c.  Diseases in which airways are affected
    -Chronic obstructive pulmonary diseases (COPD) require establishment of greater pressure gradient to move air, due to increased resistance.  COPD eventually requires large energy inputs merely to breathe.
    -Asthma caused by allergy -induced spasms of smooth muscle lining airways, plugging of airways by excess mucus secretion and thickening of airway walls due to inflammation and edema
    -Chronic bronchitis is a long-term inflammation of aiways.  It may result from exposure to chronic irritants and results in narrowing of airways due to inflammation and mucus production.  The mucus production often results in bacterial infections.
    -Emphysema (often smoking-induced) is characterized by breakdown of alveolar walls and collapse of smaller airways.  Lung tissue is broken down by trypsin which is released by alveolar macrophages.
    -Obstructive sleep apnea

  5.  Importance of pulmonary compliance and elasticity
   a.  compliance=measure of ease of stretching.  A compliant lung is one which stretches easily.
    -factors affecting compliance are tissue factors (e.g. how fibrous the tissue is) and surface tension
    -explanation of surface tension illustrated with water beading on a waxed car and movement of blood up a capillary tube.  Greater surface tension makes lung less compliant and can actually lead to collapse of lungs.  Surfactant lowers surface tension by interspersing between water molecules.
   b.  elasticity also affected by above factors.  Want a certain amount of surface tension and tension of tissue in order to have elastic recoil of lungs for expiration. 

Gas Transport in Blood
 I.  Oxygen
  A.  Transported in two ways:
   -physically dissolved in blood (1.5%)
   -bound to hemoglobin (98.5%)
 
  B.  Hemoglobin
   1.  Characteristics
    -an iron-bearing protein molecule within red blood cells that can bind as many as 4 O2 molecules
    -forms a loose, easily reversible combination with O2
    -hemoglobin saturation with O2 obeys the Law of Mass Action
    -hemoglobin also binds CO2, H+ and CO
  C.  Hemoglobin saturation
   1.  Hemoglobin is fully saturated when all of the hemoglobin present is carrying 4 O2 molecules
   2.  Influence of pO2 on saturation
     -Hemoglobin saturation curve
     -Increasing pO2 leads to increased saturation of hemoglobin in a curvilinear fashion (S-shaped curve with plateau phase and steep phase)
   3.  At high blood pO2, there is a high degree of hemoglobin saturation.  This is the situation that would be present in the pulmonary capillaries as oxygen diffuses into blood from alveolar air.  We see oxygen “loading” onto hemoglobin in the pulmonary capillary blood.
   4.  At lower blood pO2, there is a dissociation of O2 from hemoglobin.  This is the situation that would be present in tissue capillary beds as O2 diffuses out of blood into tissues, leading to low blood pO2.  This facilitates “unloading” of O2 from hemoglobin and allows delivery to tissues.
  D.  Other factors affecting saturation of hemoglobin with O2
   1.  CO2 and H+
    -both bind to the hemoglobin molecule at sites other than the heme group (where O2 binds)
    -both decrease the binding affinity of O2 to hemoglobin, thus decreasing hemoglobin saturation
    -both shift saturation curve to the right
    -the effect of CO2 and H+ on hemoglobin saturation is known as the Bohr Effect
    -important in enhancing O2 unloading at the tissue level
   2.  2,3-diphosphoglycerate
    -a product of RBC metabolism
    -reversibly binds to hemoglobin
    -enhances O2 unloading
    -2,3 DPG is increased in people living at high altitudes
    -shifts curve to right
   4.  increased temperature
    -shifts curve to right
   5.  Carbon monoxide
    -competes with O2
    -binds very strongly (50x greater than O2)
    -decreases O2 delivery to tissues
    -shifts curve left

II.  CO2 Transport
 A.  Physically dissolved (10%)
 B.  Bound to hemoglobin (30%)
  1.  Hemoglobin has a high affinity for CO2 and H+ and this is enhanced by the unloading of O2 (i.e. when O2 comes off hemoglobin, the CO2 and H+ will bind more tightly to hemoglobin).  This is known as the Haldane effect.
 C.  As bicarbonate (60%)
  1.  Reaction:
CO2 + H2O are converted to carbonic acid (H2CO3) inside red blood cells by the action of the enzyme carbonic anhydrase.  H2CO3 then dissociates into H+ and bicarbonate ions (HCO3-) which are highly soluble in blood.
  2.  Both reactions are readily reversible (carbonic anhydrase catalyzes both forward and backward reactions) and are governed by the law of mass action
  3.  When pCO2 is high, (at the level of the tissues) CO2 will diffuse into the RBC and will diffuse out of the RBC as bicarbonate ion.
  4.  At the lungs, when CO2 is diffusing from the blood into alveolar air and pCO2 is decreasing, it will favor the entry of bicarbonate into RBC, production of carbonic acid and by the action of carbonic anhydrase conversion into CO2 and water.  The CO2 can then further diffuse into the blood.
  5.  The situation with CO2 is somewhat analagous to O2 with the gas being driven into the carrier form and then released from the carrier form for diffusion.

The Haldane and Bohr effects work together to cause O2 release from hemoglobin when CO2 and H+ are high and for this O2 release to subsequently enhance the binding of CO2 and H+ ions to hemoglobin.

I.  Overview
 A.  Brainstem control of respiration
  1.  Primary control center is in the medullary region of the brainstem
  2.  Other respiratory centers in the pons of the brainstem
   a.  apneustic center
   b.  pneumotaxic
 B.  Chemoreceptors in the CNS or periphery sense pCO2, pO2, pH and send information to the brainstem to modify the rate of respiration.

II.  Medullary respiratory center
 A. Dorsal respiratory group
  1.  a neuronal cluster of inspiratory neurons with descending fibers that terminate on motor neurons supplying inspiratory muscles
  2.  these neurons have a pacemaker-like activity
  3.  firing of neurons results in inspiration.
  4.  cessation of neuronal firing results in expiration (i.e. muscle relaxation during quiet breathing)
 B.  Ventral respiratory group
  1.  a cluster of inspiratory and expiratory neurons that are inactive during quiet breathing.
  2.   Neurons become active when there is an increased need for ventilation
 

III.  Influence of Blood Chemistry on respiration
 A.  Decreased arterial pO2
  1.  Arterial pO2 is monitored by peripheral chemoreceptors (carotid and aortic bodies)
  2.  Receptors detect changes in arterial pO2 when it falls below 60 mmHg
  3.  Send afferents to medullary respiratory center to increase respiration
 B.  Increased arterial pCO2
  1.  this is the most important factor regulating ventilation under resting conditions
  2.  changes in arterial pCO2 are adjusted for by central chemoreceptors located near the medullary respiratory center
  3.  the central chemoreceptors respond to H+ rather than directly to CO2
   a.  CO2 is converted to carbonic acid by carbonic anhydrase in the brain.  The carbonic acid dissociates to H+ and bicarbonate.
   b.  Elevated H+ in the brain acts on central chemoreceptors which send afferents to the medullary respiratory center to increase ventilation and thereby reduce pCO2 in the blood.
 C.  Increased arterial H+ concentration
  1.  sensed by peripheral chemoreceptors
  2.  not sensed by central chemoreceptors because H+ does not penetrate the blood-brain barrier
  3.  increased arterial H+ stimulates ventilation which lowers pCO2 and thereby lowers arterial H+