on-Respiratory Functions of The Respiratory System | Jindal Chest Clinic

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Non-Respiratory Functions of The Respiratory
System
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INTRODUCTION

• The human respiratory tract is a complex organ
  system specialized for exchange of gases between
  environmental air and blood circulating through
  the pulmonary vascular bed.
• The respiratory system also performs a spectrum
  of important nonrespiratory functions .
• Certain of these lung functions, such as speech,
  heat and water conservation, host defense, and
  filtration of systemic blood, are a consequence
  of unique anatomic features of the respiratory
  system.

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• Functional diversity of the lungs also arises
  from a heterogeneous population of constituent
  cells that participate in water and electrolyte
  transfer, air space defense, local neuroendocrine
  regulation, xenobiotic metabolism, and excretion
  of volatile substances.
• The nonrespiratory functions of human respiratory
  tract relate to morphologic organization within
  functionally distinct compartments, including the
  conducting airways, alveolar region, and vascular
  structures.

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Non-Respiratory Functions Of the Respiratory
System

• Speech
• Heat and water conservation
• Electrolyte transport
• Host defense
• Neuroendocrine secretion
• Xenobiotic metabolism
• Surfactant synthesis and turnover
• Antioxidant defense
• Excretion of volatile substances
• Filtration
• Hemofluidity

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FUNCTIONS RELATED TO CONDUCTING AIRWAYS
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SPEECH

• Speech and language are uniquely human
  characteristics generated by coordinated activity
  of the cerebral cortex, the brain stem
  respiratory drive center, and structural
  components of the upper airway.
• Speech is composed of two mechanical functions
• phonation, which is achieved by the larynx, and
• articulation, which is achieved by the structures
  of the mouth.
• Phonation, or creation of sound, results from
  purposeful expiration of air through the vocal
  cords located within the larynx.

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• Changes in the pitch of sound emitted by the
  larynx are achieved by stretching or relaxing the
  vocal cords and by altering the shape and mass of
  vocal cord edges.
• Resonance is added by several structures,
  including the mouth, nose and paranasal sinuses,
  pharynx, and chest cavity.
• Final articulation of sound into language is
  accomplished with the lips, tongue, and soft
  palate.

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A, Anatomy of the larynx. B, Laryngeal function
in phonation, showing the positions of the vocal
cords during different types of phonation.
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HEAT AND WATER CONSERVATION

• During normal spontaneous respiration incoming
  ambient air is warmed by conduction and
  convection as it passes through the nasopharynx
  and tracheobronchial tree.
• As inspired air is warmed, it is also humidified
  by evaporation of water from the airway lining
  which transfers thermal energy to the passing air
  stream and results in net cooling of the airway
  surface.
• During expiration, temperature and vapor pressure
  gradients are reversed, and air loses thermal
  energy to the cooler airway surface.
• As air cools during expiration, its ability to
  hold water decreases, and water condenses along
  the airway surface.

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• Counter current exchange of heat and water during
  normal tidal respiration allows conditioning of
  inspired air while thermal energy and water are
  conserved during expiration.
• Under normal circumstances, tidal respiration
  results in a net loss of only about 250 mL of
  water and 350 kcal of heat from the airways in a
  24-hr period.
• Net transfer of heat and water depend on
  temperature and vapor pressure gradients between
  the airway surface and passing air stream.
• Low environmental temperatures increase
  convective cooling of the airway surface low
  humidity enhances evaporative cooling of the
  airways.
• The additional heat and water required to
  condition inspired air raise caloric requirements
  in cold climates.

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• Transfer of heat and water from the mucosal
  surface to inspired air is also related to linear
  velocity of air flow.
• Higher flow velocities are associated with lower
  rates of heat and water transfer to the air
  stream during inspiration and reduced
  condensation during expiration.
• Increases in ventilation during physical activity
  or other stresses thereby augment the net loss of
  heat and water from the mucosal surface.
• Temperature of the internal milieu can also
  affect net heat and water transfer.
• The reduction in temperature gradient between air
  leaving the lungs and the mucosal surface that
  occurs at elevated body temperatures facilitates
  water loss.

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• Net water loss in the setting of fever or
  physical exertion may actually serve as a
  mechanism for temperature regulation.
• The respiratory tract has a major role in
  temperature control in fur-bearing animals
  however, it is not thought to affect core
  temperature regulation significantly in humans
  under normal circumstances.
• Airway heat and water exchange may have important
  clinical implications in asthmatic patients, in
  whom airway cooling caused by low ambient
  temperatures or increased minute ventilation may
  provoke bronchospasm.
• Bronchoconstriction in cooler environments may
  result from acute stimulation of thermally
  sensitive body surface and mucosal receptors
  however, airway constriction in some asthmatic
  patients may outlast the duration of thermal
  receptor stimulation.

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• In this setting, bronchoconstriction is thought
  to relate to enhanced heat and water loss from
  the mucosal surface.
• Heat and water exchange in the conducting airways
  also affects the mucociliary transport mechanism.

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ELECTROLYTE TRANSPORT

• Airway epithelial cells actively transport
  electrolytes between the airway lumen and the
  interstitial compartment of the alveolar wall.
• Water absorption passively follows net Na
  transfer from the mucosal surface to the
  interstitial compartment.
• In contrast, net fluid secretion is a function of
  active epithelial cell Cl transport from the
  interstitium to the airway lumen water passively
  follows Cl movement into the lumen.
• The balance between Na absorption and Cl
  secretion, and hence net water movement, depends
  on airway region, pharmacologic intervention, and
  neurohumoral influences.

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• Furthermore, Cl secretion may be stimulated by
  several neurohumoral agents.
• The predominant direction of fluid movement under
  basal conditions is from airway lumen to
  interstitium
• Fluid accumulates in the proximal airways as
  secretions converge from distal regions of
  greater cross-sectional area via mucociliary
  transport.
• Fluid homeostasis is maintained primarily by
  absorption of Na from the airway lumen down an
  electrochemical gradient. Cl and water follow
  Na through permeable paracellular pathways.
• Net Cl secretion by epithelial cells is unusual
  under basal circumstances.

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• However, inhibition of Na absorption, with
  amiloride, for example, may shift the
  electrochemical gradient in favor of Cl
  secretion.
• Prostaglandins E2 and F2a, b-adrenergic agents,
  leukotrienes, adenosine, vasoactive intestinal
  peptide (VIP), and bradykinin stimulate
  epithelial Cl and water secretion.
• As previously noted, effective mucociliary
  clearance depends on mucosal epithelial cell
  electrolyte and fluid transport.
• Mucociliary transport forms an important defense
  against foreign material that comes in contact
  with the mucosal surface of the airway.

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• The fluid component of the mucociliary transport
  system is produced by secretory epithelial cells
  and submucosal glands.
• The clinical impact of epithelial secretory
  function is demonstrated in cystic fibrosis.
• In cystic fibrosis, abnormally increased
  epithelial Na absorption and decreased Cl
  secretion result in relatively dehydrated mucus
  and defective mucociliary transport.
• As a result, individuals with cystic fibrosis
  frequently have severe respiratory infections.

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HOST DEFENSE

• Every day the lungs are exposed to more than
  7000L of air and its fine tissues require
  protection from the daily bombardment of
  particles, including dust, pollen and pollutants,
  and the viruses and bacteria that have the
  potential, respectively, to cause lung injury or
  to invade the lung and generate lifethreatening
  infections.
• However, these problems rarely occur because the
  lung possesses very effective local protective
  mechanisms.

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Integrated System for Defense of the Respiratory Tract
Natural mechanical defenses 
  Filtration and impaction remove particles
  Sneeze, cough, and bronchospasm expel particles
  Epithelial barriers and mucus limit particle penetration
  Mucociliary escalator transports particles cephalad
Natural phagocytic defenses 
  Effected by airway, interstitial, and alveolar macrophages polymorphonuclear leukocytes
  Phagocytosis of particulates, organisms, and debris
  Microbicidal and tumoricidal activities
  Degradation of organic particles

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Integrated System for Defense of the Respiratory Tract
Acquired specific immune defenses 
  Humoral immunity
    Effected by B lymphocytes
    Biologic activities mediated by specific antibody
    Augments phagocytic and microbicidal defense mechanisms
    Initiates acute inflammatory responses
  Cell-mediated immunity
    Effected by T lymphocytes
    Biologic activities mediated by
       Delayed-type hypersensitivity reaction
       T cell cytotoxicity
    Augments microbicidal and cytotoxic activities of macrophages
    Mediates subacute, chronic, and granulomatous inflammatory responses
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FILTRATION REMOVAL OF INSPIRED
PARTICLES

• Filtration of Inspired Air
• Air passing through the nose is first filtered by
  passing through the nasal hairs, or vibrissae.
• This removes most particles larger than 10 to 15
  m in diameter. Most of the particles greater than
  10 m in diameter are removed by impacting in the
  large surface area of the nasal septum and
  turbinates .
• The inspired air stream changes direction
  abruptly at the nasopharynx so that many of these
  larger particles impact on the posterior wall of
  the pharynx because of their inertia.
• The tonsils and adenoids are located near this
  impaction site, providing immunologic defense
  against biologically active material filtered at
  this point.

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• Air entering the trachea contains few particles
  larger than 10 m, and most of these will impact
  mainly at the carina or within the bronchi.
• Sedimentation of most particles in the size range
  of 2 to 5 m occurs by gravity in the smaller
  airways, where airflow rates are extremely low.
• Thus, most of the particles between 2 to 10 m in
  diameter are removed by impaction or
  sedimentation and become trapped in the mucus
  that lines the upper airways, trachea, bronchi,
  and bronchioles.
• Smaller particles and all foreign gases reach the
  alveolar ducts and alveoli. Some smaller
  particles (0.1 m and smaller) are deposited as a
  result of Brownian motion due to their
  bombardment by gas molecules.
• The other particles, between 0.1 and 0.5 m in
  diameter, mainly stay suspended as aerosols, and
  about 80 of them are exhaled.

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REMOVAL OF FILTERED MATERIAL

• Reflexes in the Airways
• Mechanical or chemical stimulation of receptors
  in the nose, trachea, larynx, or elsewhere in the
  respiratory tract may produce bronchoconstriction
  to prevent deeper penetration of the irritant
  into the airways and may also produce a cough or
  a sneeze.
• A sneeze results from stimulation of receptors in
  the nose or nasopharynx a cough results from
  stimulation of receptors in the trachea.
• In either case, a deep inspiration, often to near
  the total lung capacity, is followed by a forced
  expiration against a closed glottis.
• The glottis opens suddenly, and pressure in the
  airways falls rapidly, resulting in compression
  of the airways and an explosive expiration, with
  linear airflow velocities said to approach the
  speed of sound.
• Such high airflow rates through the narrowed
  airways are likely to carry the irritant, along
  with some mucus, out of the respiratory tract.

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• Tracheobronchial Secretions and Mucociliary
  Transport The "Mucociliary Escalator
• The entire respiratory tract, from the upper
  airways down to the terminal bronchioles, is
  lined by a mucus-covered ciliated epithelium.
• The cilia lining the airways beat in such a way
  that the mucus covering them is always moved up
  the airway, away from the alveoli and toward the
  pharynx.
• The cilia do not appear to beat synchronously
  but instead probably produce local waves.
• The cilia beat at frequencies between 600 and 900
  beats per minute.

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• In small airways (1 to 2 mm in diameter), linear
  velocities range from 0.5 to 1 mm/min in the
  trachea and bronchi, linear velocities range from
  5 to 20 mm/min.
• The "mucociliary escalator" is an especially
  important mechanism for the removal of inhaled
  particles that come to rest in the airways.
  Material trapped in the mucus is continuously
  moved upward toward the pharynx.
• It is important to remember that patients who
  cannot clear their tracheobronchial secretions
  continue to produce secretions.
• If the secretions are not removed from the
  patient by suction or other means, airway
  obstruction will develop.

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Defense Mechanisms of the Terminal Respiratory
Units

• Inspired material that reaches the terminal
  airways and alveoli may be removed in several
  ways. These include
• Ingestion by alveolar macrophages
• Nonspecific enzymatic destruction.
• Entrance into the lymphatics and
• Immunologic reactions.

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ALVEOLAR MACROPHAGES

• Alveolar macrophages are derived from blood-borne
  monocytes that originate in the bone marrow.
• They are highly differentiated cells that
  normally patrol the alveolar lining.
• Alveolar macrophages possess marked phagocytic
  ability, being able to ingest and destroy
  pathogenic bacteria and particles
• They also have the capacity to generate mediators
  of central importance in the initiation of
  inflammation and to present antigen in the
  initiation of immune responses.
• The alveolar macrophage has a vast array of
  receptors on its surface and can respond to a
  wide range of external stimuli and subsequently
  generate a wide range of secretory products.

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• Macrophages can recognize opsonized or
  non-opsonized particles.
• Within the phagolysosome ingested particles are
  subjected to the combined destructive forces of
  both reactive oxygen intermediates generated via
  the metabolic burst and a wide range of
  degradative enzymes that have the capacity to
  digest proteins, lipids and carbohydrates
• It appears that the local intracellular
  generation of nitric oxide (NO) is an important
  defence mechanism against a variety of
  microorganisms.
• Minerals such as asbestos and quartz and a number
  of microorganisms, including Mycobacterium
  tuberculosis and trypanosomes at various stages
  of their life cycle, are able to resist
  destruction within macrophages.

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IMMUNOLOGIC RESPONSES

• Immunologic responses can be classified as
  innate immune responses (actions of macrophages,
  monocytes, lymphocytes, and granulocytes) or
  agent-specific immune responses (immunologic
  memory of T and B cells).
• The innate defense mechanisms include a
  combination of phagocytosis and cytotoxic effects
  by effector cells and activation of the
  complement cascade.
• In the adaptive response, a large population of
  antigen-specific lymphocytes is produced that
  results in a potentially greater and prolonged
  immune system response.
• The adaptive response occurs when an antigen
  derived from the toxicant exposure is processed
  and presented by a dendritic cell, macrophage, or
  monocyte to a lymphocyte.
• The lymphocyte then undergoes clonal expansion to
  produce large numbers of cells that are specific
  for the particular toxic agent. .

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• Cytotoxic T-cell production occurs by this
  process when major histocompatibility (MHC) is
  expressed by the antigen-presenting cells in
  association with toxicant-derived antigen.
• Activated T cells produce numerous cytokines,
  such as tumor necrosis factor, that significantly
  enhances the immune response and the inflammatory
  responses of resident lung cells.
• Antibodies specific to the antigen are produced
  by B cells, which are stimulated by the
  interleukins to produce memory cells and plasma
  cells.
• The pulmonary immune system differs from the
  systemic immune system in its ability to produce
  localized cell-mediated immune responses on
  repeated exposure to inhaled antigenic materials.
  
• Such localized response may play a significant
  role in hypersensitivity pneumonitis.

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XENOBIOTIC METABOLISM

• Xenobiotic metabolism is largely a function of
  the liver however, the presence of xenobiotic
  metabolizing enzymes in the human lung is well
  documented.
• These pathways generally involve both metabolic
  (phase I) and conjugative (phase II) reactions.
• Phase I reactions include oxidation(CYP 450),
  reduction, or hydrolysis they generate
  metabolites that may or may not retain
  pharmacologic activity of the original
  xenobiotic.
• Phase II reactions involve glucuronidation,
  sulfation, acetylation, or conjugation with
  glutathione or amino acids.
• These reactions render the parent xenobiotic, or
  its metabolite, water-soluble and devoid of
  pharmacologic activity.

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• Relatively low concentrations of several
  xenobiotic deactivating enzymes have been
  identified in the lung .
• The fact that the distribution of xenobiotic
  metabolizing enzymes is limited to Clara cells
  and type II alveolar epithelial cells may account
  for the relatively low levels of these enzymes in
  the lung as a whole.
• Cytochrome P450 mono-oxygenase activity has been
  localized within Clara cells of the conducting
  airways.
• Other phase I enzymes, including
  ethoxycoumarin-O-de-ethylase, a microsomal enzyme
  that catalyzes O-demethylation, and epoxide
  hydrolase, which catalyzes hydrolysis of epoxides
  arising from oxidative metabolism, have been
  identified in the lung.
• Activity of several conjugative enzymes has also
  been demonstrated in the lung these enzymes
  include glutathione-S-transferases,
  acetyltransferase, and sulfotransferases.

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• Many circulating basic lipophilic amines undergo
  first-pass retention in the lung as a result of
  endothelial metabolism.
• Significant first-pass removal has been
  demonstrated for propranolol, meperidine,
  fentanyl, and sufentanil, as examples.
• Retention and extraction of drugs is a function
  of diffusion or active transport of the substance
  into the intracellular compartment, followed by
  enzymatic modification.
• First-pass retention appears to be a partially
  saturable phenomenon, whereas overall extraction
  occurs independently of substance concentration.

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ANTI-OXIDANT DEFENSE

• By virtue of its large surface area that is
  continuously exposed to environmental air, the
  respiratory epithelium is at risk for damage
  caused by free radical oxygen metabolites.
• Generation of free radicals from exogenous
  sources may be achieved by direct interaction
  between inhaled agents and epithelial cells, and
  indirectly via activation of airway inflammatory
  cells that generate large quantities of reactive
  oxygen species.
• Endogenous oxidative metabolism also generates
  oxygen-derived free radical species that may
  interact with cell membrane phospholipid moieties
  and glycoproteins and thereby disrupt their
  structural integrity.

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• Reaction of oxygen-derived free radicals with
  cellular components is thought to contribute to
  the pathogenesis of many disease processes,
  including bronchopulmonary dysplasia, asthma,
  emphysema, pulmonary fibrosis, and ARDS (adult
  respiratory disease syndrome).
• The most biologically active oxygen species
  include superoxide, hydrogen peroxide, hydroxyl
  radical, and nitric oxide, although several other
  species have been identified.
• Free radicals may be released into the
  extracellular environment if they are produced in
  quantities that exceed intracellular scavenging
  mechanisms.
• Lung antioxidant defense mechanisms protect
  airway epithelial and other cell types from
  harmful effects of reactive oxygen species
  generated by endogenous metabolism and inhaled
  chemicals.

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• The major intracellular defense mechanisms
  against reactive oxygen species include
  superoxide dismutase, catalase, and glutathione
  redox enzymes.
• Although knowledge of antioxidant enzyme
  distribution in the human respiratory tract is
  limited, most antioxidant enzymes in the
  respiratory tract appear to be localized in the
  airways.
• Lower relative concentrations of mitochondrial
  superoxide dismutase and catalase are present in
  the bronchial epithelium.
• Extracellular superoxide dismutase is found in
  high concentrations in areas rich in type I
  collagen, in connective tissues surrounding
  smooth muscle, and in the junctions between
  epithelial cells.

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NEUROENDOCRINE FUNCTION

• Cells with neuroendocrine characteristics have
  been identified in the respiratory tract of
  humans and several other animals.
• Sensitive immunocytochemical and radiolabeling
  techniques have localized a wide variety of
  peptide mediators in the lung.

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• Neuroendocrine Epithelial Cells
• Epithelial cells that produce peptide mediators
  have been identified throughout the
  tracheobronchial tree.
• These neuroendocrine epithelial cells are
  demonstrated with silver impregnation staining or
  antibodies to general endocrine markers, such as
  chromogranin.
• Neuroendocrine epithelial cells of the airways
  share many characteristics with APUD (amine
  precursor uptake and decarboxylation) cells of
  the diffuse neuroendocrine system.
• In humans, pulmonary neuroendocrine epithelial
  cells are identified by expression of peptide
  mediators, such as gastrin-releasing peptide
  (bombesin) and serotonin.

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• In human fetal bronchi, neuroendocrine epithelial
  cells appear as early as at 8 weeks' gestation
  and may be involved in regulation of normal lung
  development.
• Peptides are expressed in a differential pattern
  during human airway development.
• Gastrin-releasing peptide is the primary peptide
  produced during early human fetal development,
  whereas calcitonin predominates later in
  development.

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• Limited evidence suggests that tracheobronchial
  neuroendocrine epithelial cells communicate with
  nonadrenergic, noncholinergic neurons located
  within the airways.
• The significance of this communication is
  unclear.
• Large numbers of neuroendocrine epithelial cells
  develop in the airways of animals subjected to
  experimental hypoxia and in humans who live at
  high altitudes.
• From these observations, it has been postulated
  that neuroendocrine epithelial cells serve a
  chemosensitive function and relay information
  about air oxygen content to the central nervous
  system.

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FUNCTIONS RELATED TO THE ALVEOLAR SPACE
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METABOLISM

• The alveolar surface is lined by two distinct
  populations of epithelial cells .
• Type I alveolar epithelial cells are thin,
  flattened cells that cover approximately 95 of
  the alveolar surface they are thought to be
  relatively quiescent metabolically and form the
  epithelial surface of the gas diffusion barrier.
• Type II alveolar cells, in contrast, are
  cuboidal, metabolically active epithelial cells
  that cover the remainder of the alveolar surface.

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• Type II alveolar epithelial cells are the source
  of pulmonary surfactant, as discussed below.
• They also demonstrate a capacity for xenobiotic
  metabolism, as well as enzyme activities that
  protect against oxidant stress.
• Type II cells secrete soluble factors that act
  locally to modulate functions of other lung
  cells, such as fibroblasts.
• These regulatory mediators may be important in
  the coordination of normal lung development, as
  well as in repair of a damaged alveolar region.
• Among soluble factors produced by type II cells
  are several eicosanoids (PGI2, PGE2, TXB2, LTB4,
  and LTC4), which may be important in regulation
  of regional blood flow and ventilation-perfusion
  matching.

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• Several investigators have shown that type II
  alveolar cells synthesize and secrete
  extracellular matrix components in vitro.
• Moreover, cultured type II cells participate in
  the turnover of their underlying substratum.
• It has been postulated that type II cell matrix
  synthesis and turnover may be important in
  repairing damaged substratum such that it will
  support restoration of differentiated alveolar
  epithelial cell function

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SURFACTANT SYNTHESIS AND TURNOVER

• Pulmonary surfactant is a complex lipoprotein
  substance forming a thin fluid film over the
  alveolar surface.
• Surfactant is a heterogeneous substance composed
  of lipid (primarily phospholipid) and specific
  surfactant-associated proteins (SP-A, SP-B, SP-C,
  and SP-D).
• Surfactant is best known for its role in lowering
  surface tension at the alveolar air-liquid
  interface more recent evidence suggests that
  surfactant is also important in host defense
  against invading organisms, and that it contains
  antioxidant enzyme activity.

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• Type II alveolar epithelial cells synthesize and
  secrete the lipid and apoprotein components
  (SP-A, SP-B, SP-C, and SP-D).
• Surfactant is stored in cytoplasmic lamellar
  bodies that fuse with the cell membrane to
  release surfactant components into the alveolar
  space by exocytosis.
• Surfactant secretion is regulated by soluble
  mediators, such as glucocorticoids and
  b-adrenergic agonists, as well as by
  intracellular second messenger signals generated
  by mechanical strain in the type II cell.

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• Following secretion, surfactant components
  transform into a three-dimensional, latticelike
  structure, tubular myelin.
• Tubular myelin is thought to be a precursor to
  the surface tension-lowering film of
  dipalmitoylphosphatidylcholine.
• Alveolar surfactant is in a constant state of
  flux it turns over every 5 to 10 hrs.
• The quantity of surfactant in the alveolar space
  is adjusted with changes in alveolar volume, so
  that an adequate reduction in surface tension is
  provided at all times.
• Adjustments in the surfactant pool occur rapidly
  alveolar surfactant can increase by 60 during
  exercise and quickly return to pre-exercise
  levels with rest.

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• Clearance of surfactant from the alveolus may
  involve uptake and resecretion, degradation and
  incorporation into new surfactant, or complete
  removal from the surfactant pool.
• It is suggested that surfactant is degraded by
  type II cells, alveolar macrophages, or within
  the surfactant fluid layer, and its degradation
  products are incorporated into newly synthesized
  surfactant components.
• Removal of surfactant from the lung may also
  occur by movement up the mucociliary escalator
  and swallowing, transfer across the alveolar
  endothelial-epithelial barrier into the lymph and
  blood, or degradation and transfer of breakdown
  products to other organs.

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Excretion of Volatile Substances

• The importance of human lung in excretion is
  readily demonstrated by its ability to eliminate
  the equivalent of more than 10,000 mEq of
  carbonic acid each day.
• Several nonrespiratory metabolites that are
  volatile at body temperature are also excreted
  from the alveolar surface.
• A large number of volatile compounds arise from
  normal endogenous metabolism and pathologic
  metabolic pathways characteristic of certain
  disease states.
• Measurement of volatile substances in expired air
  can provide useful diagnostic information
  relating to abnormal metabolic processes or
  ingestion of toxic substances.
• Measurement of breath alcohol concentration, for
  instance, is used commonly to determine the
  degree of intoxication.

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• More than 300 volatile organic compounds have
  been detected in exhaled air ,mainly hydrocarbons
  that are either aliphatic (alkanes, alkenes,
  alkynes) or aromatic (benzene) in nature.
• Cigarette smoking is a source of hydrocarbons
  such as ethene, propene, and propane.
• Hydrocarbons are primarily eliminated by
  cytochrome P450 metabolism in the liver a
  smaller number are excreted as volatile gas from
  the alveolar surface.
• Lung hydrocarbon excretion assumes a more
  important role in conditions associated with
  decreased hepatic cytochrome P450 activity.

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• Certain volatile constituents of exhaled air
  reflect specific underlying disorders of
  metabolism.
• For instance, elevated breath levels of isoprene
  have been reported in hypercholesterolemia.
• Isoprene is a breakdown product of
  dimethylallylpyrophosphate and thereby is linked
  to the synthesis of the cholesterol precursor,
  mevalonic acid.
• Methylmercaptan, a derivative of methionine
  metabolism, is excreted from the alveolar surface
  in hepatic failure and imparts a distinctive odor
  (fetor hepatis) to exhaled air.

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• The presence of acetone in exhaled breath during
  ketoacidosis is a well-known phenomenon.
• Limited glucose availability in conditions such
  as diabetes mellitus and starvation results in
  increased mobilization and oxidation of fatty
  acids.
• In turn, the production of acetoacetate, acetone,
  and/or b-hydroxybutyrate increases, and
  consequently acetone can be detected in urine and
  exhaled breath.
• Measurement of breath hydrogen concentration has
  been employed as an indicator of carbohydrate
  malabsorption bacterial breakdown of unabsorbed
  carbohydrate in the intestine releases hydrogen.

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• A large group of volatile hydrocarbons is
  generated by oxygen radical-induced peroxidation
  of cellular lipids and proteins.
• The major end products of lipid peroxidation in
  humans are ethane and pentane.
• Lipid peroxidation has been implicated in the
  pathobiology of aging and a multitude of other
  pathophysiologic processes.
• Measurement of breath hydrocarbon levels may have
  diagnostic potential in disease processes that
  involve lipid peroxidation.
• Elevated breath levels of hydrocarbons have been
  reported after acute myocardial infarction, in
  relation to lung malignancy, in cirrhosis, and in
  neurologic illnesses, including multiple
  sclerosis and schizophrenia.

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FUNCTIONS RELATED TO THE VASCULAR COMPARTMENT
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FILTRATION

• The pulmonary capillary bed serves as a filter
  that detains formed blood elements and
  particulate matter larger than the average
  capillary diameter of 8 to 10 µm.
• Pulmonary arterioles may remove larger particles
  as they taper distally into the capillary
  network.
• Filtration in the lung protects other, more
  sensitive organs, such as the brain and heart,
  from disabling, or even fatal, effects of
  particulate embolism.
• The lungs commonly remove thrombi that migrate
  from the peripheral venous circulation.
• Most of these thrombi are small and do not
  significantly compromise gas exchange function of
  the lung.

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• Filtration of cellular elements in the lung may
  provide a mechanism for modifying the cellular
  composition of circulating blood.
• Studies of venous and arterial blood demonstrate
  higher numbers of megakaryocytes in venous blood
  and greater numbers of platelets in arterial
  blood.
• These findings suggest that megakaryocytes
  released from the bone marrow are detained and
  fragmented in the pulmonary circulation.
• Both white and red blood cells are removed from
  circulating blood as it traverses the lungs.
• Lymphocytes and leukocytes may be detained in the
  pulmonary vascular bed.
• The lung also removes damaged or lysed
  erythrocytes.

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• The lung traps a number of other physiologic
  emboli, including air, fat, bone marrow, and
  fragments of placental tissue or amniotic fluid
  during pregnancy.
• Malignant cells that have migrated from other
  tissues may be captured by the lung and establish
  pulmonary metastases.
• Infectious organisms can also migrate from other
  sites and establish infection in the lung.
• Pulmonary complications of infectious emboli most
  commonly result from tricuspid or pulmonic valve
  endocarditis.
• Foreign materials, such as talc, may be filtered
  from the venous circulation in intravenous drug
  users.
• Enzymatic destruction or phagocytosis of
  particulate material in lung may prevent fatal
  embolic events in more sensitive organs, such as
  the brain.

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METABOLISM

• The pulmonary vascular endothelium forms an
  expansive blood-tissue barrier that is exposed to
  the entire volume of cardiac output and, thereby,
  is uniquely positioned for metabolic functions.
• Several peptide mediators arise from pulmonary
  vascular structures.
• Atrial natriuretic peptide (ANP) is produced,
  stored, and released from specialized myocardial
  cells that extend into the pulmonary veins.
• ANP mediates pulmonary blood vessel and airway
  smooth muscle relaxation. Pulmonary vascular
  endothelium produces a number of vasoactive and
  bronchoactive mediators.

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• Prostacyclin and endothelial-derived relaxant
  factor (EDRF/nitric oxide) have vasodilator
  properties, whereas endothelin produces
  vasoconstriction and bronchoconstriction.
• Endothelin has been shown to have trophic effects
  on smooth muscle cells and fibroblasts that may
  be important in repair of damaged lung.

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• Substances metabolised after endothelial uptake

• Substances metabolised at the edothelial surface

• Bradykinin
• Angiotensin
• Adenine nucleotides.

• Serotonin
• Prostaglandins E F
• Leukotrienes
• Norepinephrine

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• Some circulating substances are processed by lung
  endothelial cells after being transported from
  the circulation to the intracellular compartment.
• The best-known example of intracellular
  metabolism of circulating compounds is serotonin.
• Serotonin, or 5-hydroxytryptamine (5-HT), is
  primarily synthesized from tryptophan in
  endocrine cells of the gastrointestinal tract.

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• 5-HT serves as a central nervous system
  neurotransmitter its release from circulating
  platelets promotes platelet aggregation.
• After secretion by the gastrointestinal tract,
  5-HT is taken up and stored by nerve endings and
  platelets, or removed from the circulation by
  liver and lung.
• After 5-HT is taken up by endothelial cells, it
  is rapidly metabolized by monoamine oxidase and
  aldehyde dehydrogenase to physiologically
  inactive 5-hydroxyindole acetic acid (5-HIAA).
• Elevated urinary excretion of 5-HIAA is noted in
  patients with carcinoid syndrome, a neoplasm of
  endocrine argentaffin cells (APUD cells)
  characterized by oversecretion of 5-HT

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• Metabolic processing of other substances occurs
  at the cell surface without intracellular uptake.
  
• Perhaps the best-known example of a substance
  that undergoes metabolism at the cell surface is
  angiotensin.
• Angiotensin-converting enzyme, a
  carboxypeptidase, activates the vasoconstrictor,
  angiotensin II, from a decapeptide precursor
  molecule, angiotensin I.
• Angiotensin I is produced by the enzymatic action
  of renin on circulating angiotensinogen secreted
  by the liver.
• Bradykinin and adenine nucleotides also are
  inactivated at the pulmonary endothelial cell
  surface.

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HEMOFLUIDITY

• Normal respiratory functions of the lung depend
  on continuous blood flow through the pulmonary
  vascular bed.
• The entire cardiac output passes through the
  pulmonary vascular system, making these vessels
  vulnerable to damage by circulating organisms,
  toxins, and embolic material.
• Whereas injured pulmonary vessels may provide a
  nidus for bleeding or clot formation, intrinsic
  mechanisms that determine hemostasis and
  anticoagulation are modulated by the pulmonary
  vascular endothelium.
• Generation of thrombin in the lung is also
  mediated by thromboplastin.
• Thromboplastin is a phosphatide-protein complex,
  found in abundance in the lung, that augments
  conversion of prothrombin to thrombin.

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• Thrombin is involved in limitation, as well as
  initiation, of clot formation.
• Thrombin interacts with the endothelium via
  thrombomodulin to activate protein C, which
  inhibits clotting factors V and VIII and
  activates fibrinolysis.
• In addition to activating protein C, thrombin
  also initiates release of plasminogen activator
  from endothelial cells.
• Plasminogen activator in turn cleaves circulating
  plasminogen to plasmin, which digests fibrin.
• The vascular endothelium can also bind and
  inactivate thrombin furthermore, it can modify
  coagulation by releasing the vasodilator
  prostacyclin in response to thrombin.

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