Pulmonary Toxicology

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Pulmonary Toxicology

• Dr. Jena Hamra

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Structure of the Lung

• Nasopharyngeal region
• Nose, pharynx
• Filtration of particles
• Airways
• Trachea
• Bronchi
• Mucous, cilia
• Bronchioles
• Gas Exchange
• Alveoli

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Alveoli

• Epithelial cells
• Type I
• Gas exchange
• Type II
• Secrete surfactant
• No muscle fibers
• Elastin fibers
• Covered by capillaries
• Gas exchange
• Diffusion

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Gas Exchange
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Mechanisms of Lung Injury

• Oxidative damage
• Free radicals
• Reactive oxygen species
• Inflammatory response
• Macrophages, neutrophils
• Toxic gases
• Inversely related to water solubility
• Cell proliferation

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Mechanisms of Lung Injury

• Particle deposition
• Size
• Mechanics
• Ventilation rate
• Pattern of breathing
• Clearance
• Nasal blowing/wiping
• Cilia
• Phagocytosis
• Absorption

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Particulate Toxicity

• Particles are toxic
• Toxic metals and nonmetal elements
• Particle adsorb toxic chemicals and enhance
  effect
• Penetration into lungs
• Serve as condensation nuclei for water/vapors
• Overtax mucociliary apparatus
• Decrease clearance of toxic chemicals

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Types of Lung Injury

• Bronchoconstriction
• Irritation
• Cholinergic drugs
• Pulmonary edema
• Limits diffusion of gases
• Fibrosis
• Deposition of collagen
• Respiratory distress syndrome (COPD)

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Types of Lung Injury

• Emphysema
• Loss of gas exchange surface
• Enzymatic breakdown of elastin
• Asthma
• Allergic
• Cancer
• Latency period of 20-40 years

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Agents Causing Lung Injury

• Bloodborne agents
• Monocrotaline
• Pyrrolizidine alkaloid
• Reactive metabolite
• Targets endothelial cells
• 4-Ipomeanol
• Metabolized in lung to reactive metabolite
• Clara cells

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Agents Causing Lung Injury

• Bloodborne agents
• Paraquat
• Redox cycling
• Accumulates in lung tissues
• Bleomycin
• Pulmonary fibrosis
• Redox cycling

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Inhaled Agents

• Asbestos
• Hydrated silicates
• Fibers
• Uses
• Brake linings, textiles, hoses
• Electrical insulations, wall, floor and roofing
  tile
• Gas mask filters

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Asbestos

• Sources of exposure
• Manufacture of primary asbestos products
• Consumer industries
• Brake repair, shipyards
• Asbestosis
• Pulmonary fibrosis
• Cancer
• Lung cancer
• Malignant mesothelioma
• Long latency 10-30 years

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Asbestos

• Mechanism of toxicity
• Fiber phagocytized by alveolar macrophages
• Long fiber incompletely ingested
• Macrophages unable to leave alveoli
• Activate, release inflammatory mediators
• Generation of ROS

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Silica

• Component of all rocks, soils, sands and clay
• Second most abundant element in Earths crust
• Most common forms
• Free form
• Crystalline
• Quartz, granite, flint
• Combined state

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Silicosis

• Pathogenesis
• Silica particle phagocytized by alveolar
  macrophages
• Enzymatic processes convert to silicic acid
• Silicic acid reacts with lipid membranes
• Lysosomal destruction, cellular dissolution
• Acute silicosis
• High level of exposure (size lt5 mm)
• Short period (months to few years)

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Silicosis

• Chronic silicosis
• Small particles of silica (0.5-10 mm)
• Fibrogenic reaction in alveoli
• Reduced elasticity of lungs
• Decreased gas exchange
• Long latency period
• gt 10 years
• Occupational exposure
• Mining, stone cutting, ceramics

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Beryllium

• Major source of beryllium
• Beryllium aluminum silicate
• Most toxic nonradioactive element
• Source of exposure
• Industry
• Nuclear, electronic, guidance and navigation
  systems, rocket parts, heat shields, copper
  alloys
• Coal combustion

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Beryllium Health Effects

• Berylliosis
• Pulmonary and systemic granulomatous disease
• Inflammatory response
• Due to inhalation of dust
• Long latency period
• 10 15 years
• Symptoms
• Dyspnea, fatigue, cough, weight loss, pulmonary
  hypertension