TOXICOLOGY OF THE LUNG (2)

¡¡

¡¡

I. Pulmonary Anatomy and Ultrastructure

The lung is organized into 3 compartments: airways, blood vessels, and conective tissue. We can think of it as 2 systems of tubes (airways and vasculature) cemented together by the third compartment (inteerstitium):

- Airways and airsacs (traqueobronquial tree and alveoli),

- Vasculature (2 systems, bronquial and pulmonary)

- Interstitium (systems: lymphatic, nervous; cellular: fibroblasts, muscle, nerve cells; extracellular: collagen, elastin)

The following slides review the overall gross anatomy and hystology of the lung and its cell types, examine some of its morphometric (quantitative) features, and show some structural features revealed by specialized morphological techniques.

A. Structural schema

Slide 1. Netter, p. 3. Respiratory system. Note the distinction between the upper and lower respiratory systems. The function of the nasal passages: inhaled air is "conditioned", ie, warmed and humidified and it can also be the site of toxic action, e. g., formaldehyde.

Slide2. Netter, p. 16. Bronchopulmonary segments. Lobes of human lung: 3 right lobes with 10 segments and 2 left lobes with 9 segments. Major airways on right are straighter than those on left.

Slide3. Netter, p. 24. Intrapulmonary airways.

Slide4. Intrapulmonary blood circulation.

Slide 5. Drawing of 3 levels of respiratory epithelium - alveolus, bronchiole, bronchi- with continuous airway lining fluid. In: Bergofsky. '91 Am J Med 91: 4s-10s.

¡¡

B. Ultrastructure and morphometry

Slide6. Netter, p. 26. Ultrastructure of respiratory epithelium.

Slide7. E. M. of bronchiolar epithelium.

Slide8. SEM of airway surface of adult monkey.

Slide9. SEM of fetal monkey lung with bronchial displasia.

Slide 10. Netter, p. 29. Ultrastructure of alveolar capillary unit.

Slide 11. Netter, p. 30. Ultrastructure of the type II cell and surfactant secretion.

Slide 12. Drawing of mucocilliary blanket. In: Vander et al '70 Human Physiology. The arrows indicate the upward direction in which the cilia move the overriding layer of mucus, to which foreign particles are stuck.

Slide 13. Low mag SEM of mucous blanket in rat.

Slide 14. Higher mag SEM of mucous blanket.

Slide 15. TEM of mucous blanket.

¡¡

C. Specialized techniques

Slide 16. Airway cast-untrimmed.

Slide 17. Airway cast-trimmed.

Slide 18. Plastic cast of the conducting airways from traquea to terminal bronchioles, different color in each lobe.

Slide 19. Low mag SEM of vascular cast.

Slide 20. Higher mag SEM of vascular cast.

¡¡

¡¡

¡¡

Cell Types in Normal Lung

More than 40 cell types have been identified (Breeze & Wheeldon, Am Rev Resp Dis, '77).

HISTOLOGICAL FEATURES OF LOWER RESPIRATORY SYSTEM

¡¡

MORPHOMETRY OF HUMAN LUNG

¡¡

(NP = "non-parenchyma"; versus "parenchyma"the gas exchange portion of the lungmade up of alveoli, capillaries and connective tissue)

Surface Area:

where: SA = alveolar surface area

¡¡

¡¡

TOXICOLOGY OF THE LUNG (2)
Summary of characteristics of human lung diseases


Inflammation: Acute or chronic response to cell/tissue injury; accompanied by influx of inflammatory cells (macrophages, neutrophils, lymphocytes) and mediator release (interleukins, cytokines).

Bronchitis/Bronchiolitis: Inflammation of airways; enlargement of mucous glands and increased mucous cells; accompanied by airway narrowing by mucous plugs and air blockage, edema, inflammation, and fibrosis.

Edema: Leakage of fluid from vascular compartment to interstitial and air compartments.

Bronchial asthma: Heightened reactivity of bronchial tree to stimuli leading to bronchial constriction and inflammation. Wheezing, cough, dyspnea, and tenacious sputum may be present.

Emphysema: Destruction of and permanent loss of septal walls of alveoli, alveolar ducts, and respiratory bronchioles.

Allergic alveolitis (hypersensitivity pneumonitis): Tissue reaction to inhaled antigenic organic aerosols; leads to infiltration of lung by inflammatory cells and can result in edema, fibrosis, and emphysema.

Fibrosis: Irreversible thickening of alveolar septa/airways by formation of fibrotic (scar-like) tissue; may be associated with edema, presence of inflammatory cell response.


Acute airway injury

Bronchoconstriction (airway hyperresponsiveness)

 

due to contraction of airway smooth muscle
(example: response of asthmatics to SO2 inhalation)

may also be associated with airway inflammation

Airway inflammation

 

injured epithelial cells: 1) release membrane constituents such as arachidonic acid that generate cyclooxygenase and lipoxygenase products; 2) produce vasoactive mediators; 3) release chemotactic factors that attract other effe ctor cells, e.g., neutrophils

vasoactive mediators increase vascular permeability, leads to edema formation

hypersecretion of mucous and serous fluids into airways

 

Impairment of defense mechanisms

decreased mucociliary clearance, due to injury to ciliated cells or changes in chemical properties and composition of mucous layer

Acute lung (parenchymal) injury

Type I cell injury and cell death

 

repaired by dedifferentiation and mitotic response of type II cells

 

Impairment of alveolar macrophage function

 

may lead in turn to increase in respiratory illness because of lower defense against microorganism

 

antibacterial defense mechanisms impaired by exposures to as little as 0.1 ppm O3 although O3 exposure does not appear to affect antiviral defense

 

Release of mediators, influx and activation of cells

 

quantitation of such mediators and cells the basis for the alveolar lavage assay

General sequence of acute inflammatory response

• Release of mediators and chemotactic factors by activated macrophages and/or injured epithelial cells
• Causes influx of neutrophils (PMNs).
• The neutrophil is the signal cell of acute inflammationthe "pluripotent inflammatory cell"
• Other cells in the pulmonary inflammatory response:
  • mast cells (particularly, allergic responses to antigenic stimuli)
  • eosinophils (in response to proteases, toxic oxygen free radical species, eicosanoids)

Chronic obstructive airway disease

Two major obstructive diseases:

1) Bronchi al asthma

• Inflammation involved but unlikely a single common mechanism given the diversity of causative agents
• Associated with occupational exposures (e.g., red cedar dust, toluene diisocyanate, metal salts), ambient air pollution, air toxics, dust mites, animal dander, impaired health status

2) Chronic obstructive pulmonary disease (COPD)

A) Chronic bronchitis (clinical state: pink puffers)

• Excess mucous production
• Clearly associated with cigarette smoking and air pollution

B) Emphysema (clinical state: blue bloaters)

• Not an obstructive airway disease per se but often associated with chronic bronchitis by destruction of alveolar walls
• Increased release of elastase by neutrophils and macrophages, and/or decreased antiprotease activity
• Clearly associated with heavy cigarette smoking

¡¡

¡¡

Chronic lung disease (fibrosis)

• Particularly associated with chronic inhalation of mineral dusts such as silica, asbestos, and other occupational dusts, e.g., aluminum dust, coal dust
• Fibrotic process generates a group of inter-stitial lung diseases collectively termed "pneumoconioses"
  
  

  Fiber	Disease
  asbestos	asbestosis (white lung)
  silica	silicosis
  cotton dust	byssinosis (brown lung)
  aluminum dust	aluminosis
  tin	stanosis
  coal dust	pneumonconiosis (black lung)

  
  
  

• As the neutrophil is the key cell type in acute inflammatory injury, the alveolar macrophage is central to chronic lung injury and fibrosis
• Phagocytosis of dust particles activates alveolar macrophages and results in release of mediators, chemo-tactic factors, toxic oxygen species and proteases

¡¡

The lung's defense against environmental pollutants

• Nonspecific defenses
  • Filtration and impaction
  • Mucociliary system
  • Sneezing and coughing
  • Epithelial barriers
  • Phagocytosis
    • Performed by alveolar macrophages and polymorphonuclear leukocytes (ingesting particles, killing microbial organisms,presenting antigen to lymphocytes)
• Specific immune defenses
  • Humoral immunity
    • Performed by B lymphocytes and mediated by specific antibodies (IgA, IgG, IgE)
• Cell-mediated immunity
  • Performed by T lymphocytes; includes delayed hypersensitivity reaction and T-cell cytotoxicity
• Biochemical defenses
  • Protective proteins
    • a1-antitrypsin, a2-macroglobulin, etc.
  • Antioxidant mechanisms
    • Antioxidant enzyme systems, i.e., catalase, superoxide dismutases, enzymes of the glutathione redox cycle.
    • Fat-soluble antioxidants, i.e., vitamin E, b-carotene, bilirubin.
    • Water-soluble antioxidants, i.e., vitamin C, uric acid, cysteine, etc.
• Pulmonary metabolism of xenobiotics
  • Mixed-function oxidases present in type II, Clara, tracheal bronchial epithelial and ciliated cells and pulmonary macrophages. In: Principles & Practice of Environmental Medicine, AB Tarcher, ed (1992), p. 104

MAJOR PULMONARY OXIDANT SCAVENGERSa

• Enzyme

  Catalase	Catalyzes dismutation of H2O2, reduces methyl and ethyl hydroperoxides.
  Superoxide dismutases	Catalyze dismutation of ·O2 to H2O2
  GSH redox cycle GSH peroxidase	Catalyzes reduction of H2O2 and other hydroperoxides (lipid peroxides, lipoxygenase products).
  GSH reductase	Catalyzes reduction of low-molecular weight disulfides.
  G-6-PD and 6- phosphogluconate dehydrogenase	Supply NADPH to the GSH redox cycle.

• Fat-soluble compounds

  Vitamin E	Converts ·O2, ·OH, and lipid peroxyl radicals to less reactive forms. Breaks lipid peroxidation chain reactions.
  b-carotene	Scavenges ·O2, reacts directly with peroxyl radicals.
  Bilirubin	Chain-breaking antioxidant. Reacts with ROO?

• Water-soluble compounds

  Vitamin C	Directly scavenges ·O2 and ·OH. Neutralizes oxidants from stimulated neutrophils. Contributes to regeneration of vitamin E.
  Uric acid	Scavenges ·OH, ·O2, oxoheme oxidants, and peroxyl radicals. Prevents oxidation of vitamin C. Binds transition metals
  Glucose	Scavenges ·OH
  Cysteine	Reduces various organic compounds by donating electron from sulfhydryl groups.
  Cysteamine	Same as cysteine
  GSH	In addition to role as substrate in GSH redox cycle, reacts directly with ·O2, ·OH, and organic free radicals.
  Taurine	Conjugates xenobiotics, reacts with HOCL.

• High-molecular-weight antioxidants

  Tracheobronchial mucus	Scavenges inhaled oxidants.
  Albumin	Binds transition metals. Reacts with oxidants as a "sacrificial" antioxidant.

  
  

• Definition of abbreviations: GSH, glutathione; H2O2, hydrogen peroxide; ·OH, hydroxyl radical; ·O2. superoxide anion; Cu, copper; Zn, zinc; Mn, manganese; SOD, superoxide dismutase; G-6-PD, glucose-6-phosphate dehydrogenase; NADPH, nicotinamide adenine dinucleotide phosphate; O2, singlet oxygen; HOCl, hypochlorous acid.

a In: Principles & Practice of Envir. Med. AB Tarcher, ed (1992), p. 113.

Plumonary Function Tests

LINKS OF INTEREST

Link 1: Pulmonary pathology slides; some interesting ones about emphysema, mesothelioma, etc.

Link2.

¡¡