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Questions and Answers
What is the primary function of the nasal passage as the first line of defense against toxic respiratory insults?
What is the primary function of the nasal passage as the first line of defense against toxic respiratory insults?
What leads to the induction of CYP450 2B1 and 4B1 in the nasal mucosa?
What leads to the induction of CYP450 2B1 and 4B1 in the nasal mucosa?
What are the effects observed in the olfactory region after exposure to 400 ppm methyl methacrylate?
What are the effects observed in the olfactory region after exposure to 400 ppm methyl methacrylate?
What is a significant feature of the conducting airways' epithelial structure?
What is a significant feature of the conducting airways' epithelial structure?
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What function does the mucous layer in the conducting airways serve?
What function does the mucous layer in the conducting airways serve?
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Which size of silica particles is most likely to trigger inflammation and cancer more effectively?
Which size of silica particles is most likely to trigger inflammation and cancer more effectively?
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What condition is caused by asbestos exposure and characterized by lung scarring?
What condition is caused by asbestos exposure and characterized by lung scarring?
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Which chemical compound is known to induce extensive lung injury when ingested?
Which chemical compound is known to induce extensive lung injury when ingested?
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What role do polymorphonuclear cells play in the body regarding lung health?
What role do polymorphonuclear cells play in the body regarding lung health?
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What is a primary toxic effect of cyclophosphamide on lung tissue?
What is a primary toxic effect of cyclophosphamide on lung tissue?
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What synergistic effects could result from the combination of inorganic particles and a biological compound?
What synergistic effects could result from the combination of inorganic particles and a biological compound?
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Which lung disease is specifically linked to exposure to silica particles?
Which lung disease is specifically linked to exposure to silica particles?
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What form of lung injury is caused by monocrotaline over time?
What form of lung injury is caused by monocrotaline over time?
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What is the primary function of Clara cells in the respiratory zone?
What is the primary function of Clara cells in the respiratory zone?
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Which type of cell serves as a stem cell pool for replacement and repair in the airways?
Which type of cell serves as a stem cell pool for replacement and repair in the airways?
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Which particle size is most likely to penetrate epithelial membranes in the lungs?
Which particle size is most likely to penetrate epithelial membranes in the lungs?
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What is the key function of pulmonary neuroendocrine cells (PNECs) in the lung?
What is the key function of pulmonary neuroendocrine cells (PNECs) in the lung?
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What is the first step in the lung's defense mechanism for clearing deposited particles?
What is the first step in the lung's defense mechanism for clearing deposited particles?
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Which determinant of toxic effect correlates with daily mortality rates during smog episodes?
Which determinant of toxic effect correlates with daily mortality rates during smog episodes?
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What mechanism is primarily involved in the clearing of small particles in the lungs?
What mechanism is primarily involved in the clearing of small particles in the lungs?
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In which part of the respiratory system does gas exchange primarily occur?
In which part of the respiratory system does gas exchange primarily occur?
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What is the effect of low dose cyclophosphamide when used for treating paraquat pulmonary toxicity?
What is the effect of low dose cyclophosphamide when used for treating paraquat pulmonary toxicity?
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Which of the following is NOT a consequence of pulmonary edema?
Which of the following is NOT a consequence of pulmonary edema?
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What leads to fibrosis in lung tissue?
What leads to fibrosis in lung tissue?
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Which agent is primarily associated with causing emphysema?
Which agent is primarily associated with causing emphysema?
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Which factor does NOT influence the hazard associated with airborne particulates?
Which factor does NOT influence the hazard associated with airborne particulates?
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What is a significant biochemical consequence of the inhalation of irritant gases?
What is a significant biochemical consequence of the inhalation of irritant gases?
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Why are the kidneys particularly vulnerable to toxic substances?
Why are the kidneys particularly vulnerable to toxic substances?
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Which response describes a significant consequence of lung cancer?
Which response describes a significant consequence of lung cancer?
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What is the most common site of toxicant-induced renal injury?
What is the most common site of toxicant-induced renal injury?
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Which of the following is an example of a mycotoxin?
Which of the following is an example of a mycotoxin?
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What class of nephrotoxins does mercury belong to?
What class of nephrotoxins does mercury belong to?
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Which nephrotoxin is known for impairing glomerular ultrafiltration?
Which nephrotoxin is known for impairing glomerular ultrafiltration?
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What is a potential consequence of cadmium exposure in the kidneys?
What is a potential consequence of cadmium exposure in the kidneys?
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Which agents are considered therapeutic nephrotoxins?
Which agents are considered therapeutic nephrotoxins?
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Which nephrotoxin is associated with altered hemodynamics due to indirect effects?
Which nephrotoxin is associated with altered hemodynamics due to indirect effects?
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What is a characteristic of distal tubule injury in nephrotoxicity?
What is a characteristic of distal tubule injury in nephrotoxicity?
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What role do cell-cell junctions play in the nephron's architecture?
What role do cell-cell junctions play in the nephron's architecture?
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What is a consequence of cadmium exposure in kidney cells?
What is a consequence of cadmium exposure in kidney cells?
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What is the primary mechanism by which NSAIDs can lead to acute renal failure?
What is the primary mechanism by which NSAIDs can lead to acute renal failure?
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Which type of nephropathy is characterized by oxidative stress and chronic damage?
Which type of nephropathy is characterized by oxidative stress and chronic damage?
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What leads to crystal nephropathy?
What leads to crystal nephropathy?
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What common effect does nephrotoxicity have on kidney function?
What common effect does nephrotoxicity have on kidney function?
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Which situation best illustrates a direct chemical insult to the kidneys?
Which situation best illustrates a direct chemical insult to the kidneys?
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What structural component of the kidney is primarily affected by nephrotoxic agents?
What structural component of the kidney is primarily affected by nephrotoxic agents?
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Study Notes
Toxic Responses of the Respiratory System
- The respiratory system's first line of defense against toxic insults is the nasal passage.
- Particles are filtered by diffusion or impaction onto nasal mucosa.
- Nasal mucosa possesses CYP450 enzymes for metabolism, allowing it to match the challenges posed by low air quality.
- This makes the mucosa a target for metabolically induced lesions.
- The conducting airways consist of pseudostratified epithelium containing ciliated and non-ciliated cells, which become simple cuboidal as the tract descends.
- Mucous (goblet) cells produce glandular tract mucus.
- Mucous layers provide antioxidant, acid-neutralizing, and free radical-scavenging functions to protect epithelial cells.
- Conducting airways progressively divide into narrower, shorter, and more numerous tubes.
- Epithelial cells are increasingly interspersed with Clara cells, which secrete protective and regulatory peptides to detoxify distal airways.
- Clara cells also contain xenobiotic enzymes.
- The gas-exchange region branches into bronchioles and alveolar ducts/sacs, facilitating gas exchange.
- Clara cells are highly concentrated in terminal bronchioles.
- Cellular composition varies along the airways, with ciliated cells, Clara cells, pulmonary neuroendocrine cells (PNECs), basal cells, and goblet cells.
- PNECs secrete active peptides, playing regulatory and growth/repair roles.
- Basal cells are stem cells responsible for replacement and repair.
- Nasal clearance removes particles rapidly, depending on size.
- Tracheobronchial clearance involves mucous, but cellular injury can impair it.
- Pulmonary clearance includes trapping in a fluid layer, phagocytosis by macrophages in mucous and alveolar macrophages, and removal via lymphatic drainage.
- Small particles penetrate epithelial membranes, dissolve, and are removed in the bloodstream.
- Distinct mechanisms are matched to specific challenges; toxic consequences increase with airway penetration and removal difficulty.
Types of Toxic Particles
- Combustion processes, such as diesel engines, create primary and aggregate elemental carbon, ultrafine particles, and metals.
- Secondary atmospheric chemistry produces particles like sulfates, nitrates, and chlorides.
- Fossil fuel combustion leads to fly ash, metals, and materials like mullite and glass.
- Natural minerals, soil, and wind-blown materials contribute to air pollution.
- Biological sources include bacteria, spores, organic carbon debris, and products like 2° cigarette smoke (with components such as PAH, acrolein, and nitroso compounds).
Determinants of Toxic Effect: Exposure Quantity
- A correlation exists between daily mortality rates and particle concentrations during London Smog episodes (1958-1972).
- Exposure length significantly impacts toxic effects.
Determinants of Toxic Effect: Particle Size
- Ultrafine particles (50nm) and fine colloidal particles (480nm) have differing effects. Fine particles are more difficult to remove by the body's defenses compared to smaller particles.
Size Makes a BIG Difference!
- Smaller particles penetrate deeper into the lungs, triggering inflammation and cancer more effectively, and are more difficult to remove.
- Larger particles tend to remain more superficial in the airways.
Combined Insults Can Be Synergistic
- Combining inorganic particles with biological components like endotoxin can have synergistic effects, increasing the immune response and toxicity compared to either insult alone.
- Polymorphonuclear cells (PMNs) with phagocytic activity are relevant markers for acute inflammatory responses.
Specific Toxicants: Airborne Agents
- Asbestos causes asbestosis, lung cancer, and malignant mesothelioma depending on fibre length, diameter, and iron content (different fibres have different impacts).
- Silica causes silicosis (acute or chronic).
- Naphthalene causes necrosis in tissues.
Specific Toxicants: Blood Borne Agents
- Paraquat (pesticide) induces extensive lung injury (fibrosis) by targeting type I and II alveolar cells and interfering with electron transfer and reactive oxygen species.
- Monocrotaline, a naturally occurring plant product, damages specific endothelial cells lining pulmonary vasculature.
- Low dose cyclophosphamide treats paraquat pulmonary toxicity by targeting and killing paraquat-affected cells in the lungs to clear the area.
Responses to Lung Injury
- Airway reactivity includes reflex constriction, stimulated decrease in airway diameter due to irritant gases or cigarette smoke.
- Pulmonary edema arises from thickened alveolar capillary barriers due to inflammation and tissue proliferation. This reduced exchange and compromised function.
- Inflammation from allergic reactions or chemicals like NO2 and phosgene, or mechanical factors, can injure the lungs.
- Fibrosis involves collagen deposition, causing the lung to shrink and stiffen.
- Emphysema is characterized by abnormal enlargement of airspaces, macrophage accumulation, and destruction of alveolar walls.
- Hyper-inflated lungs can't effectively exchange oxygen and carbon dioxide.
- Asthma involves narrowed airways due to provoking agents like dust and pollen.
- Lung cancer involves malignant tissue growth, obstructing lung function (common causes include cigarette smoking and asbestos fibres/metallic dusts).
Summary of Respiratory System Toxicity
- Four main factors determine the degree of harm from airborne particles: type, concentration, particle size (small is usually bad), and duration of exposure.
- Biological effects include systemic toxicity, allergies, and hypersensitivity, as well as carcinogenesis, and irritation of mucous membranes.
- The respiratory system is highly repairable and can handle many toxic environmental insults.
Toxic Responses of the Renal System
- The kidney's high blood flow (25% cardiac output; GFR 120 mL per minute) and concentrated urine production make it a target for toxicants.
- The kidney is also a site for xenobiotic metabolism; the proximal tubule is particularly vulnerable due to leaking (e.g., from antibiotics, halogenated hydrocarbons, mycotoxins, heavy metals).
Nephrotoxicity
- Nephrotoxins have various causes including direct chemical toxicity, altered haemodynamics, and pH-dependent crystallization.
- Heavy metals, halogenated hydrocarbons, therapeutic agents (e.g., aminoglycosides, cisplatin, amphotericin B, cyclosporin, NSAIDs), mycotoxins (e.g., aflatoxin), and their impacts on kidney function are relevant here.
Specific Sites of Nephrotoxicity
- Glomerular injury can alter glomerular permeability to proteins (e.g. doxorubicin), and impair glomerular ultrafiltration (e.g. amphotericin B and cyclosporin).
- Proximal tubule injury is a common site for toxicant-induced renal injury, influenced by transport and accumulation of toxicants (e.g., aminoglycosides, Beta-lactam antibiotics, cisplatin, and metals). There are segmental differences in transport within the proximal tubule as well as in the activation of CYP450s and 𝛽-lyase activity.
- Distal tubule injury is less common and affects concentrating ability and acidification (e.g. amphotericin B).
Nephrotoxicity Examples (Specific Mechanisms)
- Direct chemical toxicity Cadmium interacts with the extracellular Ca2+ binding domains/E-Cadherin, impacting their adhesive properties and disrupting cadherin-dependent cell-cell junctions. This disrupts the integrity of cell-cell junctions, which are critical to the structure and function of the nephron.
- Haemodynamic failure (e.g., NSAIDs) impacting the kidney by reducing renal blood flow. It can cause acute renal failure (reversible with large doses), and chronic cases lead to Analgesic nephropathy (oxidative stress and necrosis), and Interstitial nephritis (rare) inflammation and oedema in the kidney.
- Crystal nephropathy occurs due to compound insolubility in urine, reducing intravascular volume, impacting GFR, and altering urine pH. This forms crystals which obstruct kidney function (e.g., antivirals, antibacterial and anti-cancer agents).
Summary of Renal Toxicity
- The kidney is vulnerable to toxic insults due to its function, high blood flow, and exposure/accumulation.
- Sites and mechanisms of damage are important, specifically those linked to glomerulus, proximal tubule and distal tubule.
- Common mechanisms involve direct chemical insult, haemodynamic disruption, and crystallization.
- The complex structure and function contribute to the kidney as a common target for toxicity.
Reading List
- Casarett & Doull's Toxicology: Chapter 14 (Kidney) and Chapter 15 (Respiratory system).
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Description
This quiz explores the defenses of the respiratory system against toxic insults, focusing on the roles of nasal mucosa and conducting airways. It covers how different epithelial cells, including goblet and Clara cells, contribute to respiratory health by detoxifying and protecting airway tissues. Test your understanding of respiratory anatomy and functions!
