Lung Toxicity - Lung Defenses

							Lung Toxicity - 1B: Lung Defenses
Problems of lung functional anatomy: • epithelial cells lining airways and alveoli are not highly exfoliative
– require specific cellular regeneration & repair after serious damage

• lung immmune cells (macrophages, neutrophils) can produce lung damage
– can produce inflammatory mediators and cytokines, reactive oxygen species (ROS)

• lungs often exposed to high conc of reactive oxygen species (ROS)
– external - oxidant gases such as ozone and NOx – internal - produced by lung cells/tissues in response to irritants or noxious agents

F2007

HLTH 350 Lecture 1B

1

Normal air flow and gas exchange in lung alveoli
• special vulnerabilities of lung to air contaminants
– large tidal volume of external air (roughly 8 cu meters per day) – tidal air flow -- not a flow-through system -- airborne particles can accumulate

– branching and narrowing of airways traps particulate matter

F2007

HLTH 350 Lecture 1B

2

Air:blood interface
• air:blood interface in alveolar wall comprises very thin partition
– swelling or thickening of alveolar wall interferes with gas-exchange – small lung airways (bronchioles) lack rigidity, tend to collapse easily – alveolar structures are inherently unstable, susceptible to collapse – deficient / inactivated pulmonary surfactant can lead to collapse

• ventilation:perfusion ratio - ventilation = rateof airflow into alveoli --> exchange of respiratory gases (O2and CO2) between atmosphere and lungs - perfusion = rate of capillary blood flow in alveoli

• abnormalities in ventilation:perfusion ratio - airway obstruction / alveolar wall thickening --> ventilation inadequate - alveolar capillary damage --> perfusion inadequate
F2007 HLTH 350 Lecture 1B 3

Role of lung in gas exchange

F2007

HLTH 350 Lecture 1B

4

Lung defense mechanisms
• lungs rely on several defense mechanisms to avoid damage
– aerodynamic filtration
• defensive - filters out some particles in upper airways; protects parenchyma • harmful- deposits other particles in lower airways; small airway damage

– mucociliary escalator
• defensive - traps and removes particles and bacteria from airways • harmful - excessive mucus secretions; can reduce airflow

– airway reflexes (cough, bronchoconstriction)
• defensive - reduces penetration of particles into distal lung regions • harmful - may reduce airflow in large or small airways

– pulmonary alveolar macrophages (PAMs)
• defensive - PAMs ingest and destroy many bacteria • damage - PAMs may release harmful enzymes and inflammatory cytokines

• imbalances between defense and damage can lead to lung disease
F2007 HLTH 350 Lecture 1B 5

Particle Factors - terminology
• particle size - mass median aerodynamic diameter (MMAD)
– inhalable particulates (IP)
• particles filtered out in upper airways • nasal passages, nasopharynx, trachea, and bronchi • diameter 10 uM - 2.5 uM (PM10) “coarse fraction”

– respirable particulates (RP)
• diameter 2.5 - 0.1 uM (PM2.5) “fine fraction” • diameter < 0.1 uM (PM0.1) “ultrafine fraction”

• particle shape
– aspect ratio = ratio of length/diameter – low aspect ratio = compact particulates – high aspect ratio = fibrous particulates
• long thin fibers penetrate deeply into distal lung

• solubility - insoluble particles more persistent in lung tissues • toxicity - “benign” (relatively inert) or “fibrogenic” (toxic)
F2007 HLTH 350 Lecture 1B 6

Aerodynamic filtration of particles
• impaction
– coarse fraction particles (>2.5 uM) – deposited in Region of Turbulent Flow (nose, throat, and bronchi) – impact with walls of nasal passages and upper airways
• sticks to mucus in nose & airway membranes; mechanical expulsion (e.g. sneeze)

• sedimentation
– fine fraction particles (2.5 - 0.1 uM) – deposited in Region of Laminar Flow
• airflow progressively slows and smooths as airways narrow (bronchioles, alveoli)

– particles settle out by gravitational deposition; particle retention often harmful

• molecular diffusion (Brownian motion)
– ultrafine fraction (<0.1 uM) – similar to gas molecules -- random motion with little gravitational settling – deposition by random impacts with alveolar surface; variable retention
F2007 HLTH 350 Lecture 1B 7

Section of bronchiolar mucosa (high magnification ultramicrograph - false color)

A layer of ciliated epithelial cells (green hairs ) is interspersed with mucus-producing goblet cells covered with microvilli (yellow). Cilia and mucus -- the MC escalator -- form the main mechanical line of defense against environmental invaders of the lung airways
F2007 HLTH 350 Lecture 1B 8

Mucociliary (MC) escalator
• airway mucosa - thin layer of epithelial tissue lining airways
– mainly comprised of ciliated epithelium cells
• cilia = fine hair-like projections on apical surface

– goblet cells and mucus gland cells (also possibly clara cells)
• secrete mucus onto surface of mucosal lining

• lung mucus secretions have 2 component layers
– hypophase - lower sol layer of serous (watery) secretion
• cilia propel mucus hypophase in upward direction

– epiphase - upper gel layer of mucus (viscous) secretion
• traps and immobilizes dust and bacterial particles

• MC escalator carries mucus upward from lower to upper airways
– cilia beat in rhythmic waves
• provides propulsion for hypophase -- epiphase carried along passively

– expulsion mechanism for mucus and trapped particles
F2007 HLTH 350 Lecture 1B 9

Bronchial mucosa (H&E stain) comprised of several types of epithelial cells
Airway lumen

cilia on apical cell surface goblet cell (rare)
ciliated columnar epithelial cells (common)

basal cell layer
basement membrane

submucosa - connective tissue
F2007 HLTH 350 Lecture 1B 10

Schematic view of mucociliary escalator

F2007

HLTH 350 Lecture 1B

11

Airway reflexes - cough
• involuntary reflex induced by irritation of lung airways
– reflex nerve stimulus from brainstem cough center

• sudden forceful contraction of diaphragm and rib muscles
– strong intra-thoracic pressure on lung tissues

• rapid expulsion of air from upper lung airways
– eliminates mucus from upper airways

• potential problems
– airflow rapid only in upper (large) airways – ineffective in clearing mucus from small airways – lung compression may collapse small airways
F2007 HLTH 350 Lecture 1B 12

Airway reflexes - bronchoconstriction
• involuntary autonomic reflex
– acute irritation of lung airways by noxious agents – immunological hypersensitivity reaction (e.g. asthma, anaphylaxis) – physiological stimuli or drug reactions

• smooth muscle fibers spiral wrapped around airways
– muscle fibers contract by autonomic nervous system stimulation (vagus n.) – narrows lumen (air passage) of airways

• inflammatory mediators (e.g. histamine) produce mucosal edema (swelling)
– narrows lumen of airways

• mucus secretions
– contribute to reduced airflow

• breathing difficulties
– dyspnea (shortness of breath), wheezing, partial asphyxia
F2007 HLTH 350 Lecture 1B 13