Target Organ Toxicity (Respiratory System) PDF

Toxic responses of the respiratory system Nasal passage 1st line of defence against toxic respiratory insult Function: Simple particulate filter Smooth, pressurised air flow...

Toxic responses of the respiratory system Nasal passage 1st line of defence against toxic respiratory insult Function: Simple particulate filter Smooth, pressurised air flow Warms and humidifies air - Particles filtered by diffusion or impaction onto nasal mucosa - Mucosa possesses CYP450 2B1 and 4B1 for metabolism  induced by low air quality, so defences match challenge - Therefore, target for metabolically induced lesions.  Nasal (olfactory) toxicity Olfactory region after 1 day exposure to 400 ppm methyl methacrylate (volatile liquid used in industry as a monomer in production of high MW polymers) showing regions of olfactory epithelial degeneration and necrosis. Control Exposed Turbinates (nasal conchae) Grainy due to tissue damage, Clean image, smooth and shrivelled and narrowed clearly defined conchae conchae Hext et al (2001) Toxicology 156, 119–128  Conducting airways Conducting airways: Pseudo stratified epithelium containing ciliated and non-ciliated cells (mucous and serous cells)  simple cuboidal as tract descends Mucous (goblet) cells produce glandular tract mucus Mucous layer antioxidant, acid neutralising and free radical scavenging functions – protect epithelial cells  Conducting airways Progressive division of tubes: trachea  2 bronchi etc. Produces narrower, shorter and more numerous tubes Epithelium increasingly interspersed with Clara cells  secrete protective, regulatory peptide solution that detoxifies distal airways, also contain xenobiotic enzymes  Respiratory zone Gas–exchange region: Branching eventually leads to bronchioles and alveolar ducts/sacs where gas exchange takes place Clara cells highly concentrated in terminal bronchioles  Cellular composition of the airways Pseudostratified Cuboidal Goblet cells Clara cells PNEC (pulmonary neuroendocrine cell)  secrete active peptides  paracrine regulator/hypoxia monitor/growth and repair control Basal cells – stem cell pool for replacement and repair  Clearing deposited particles is key aspect of lung’s defence 1. Nasal clearance Rapid removal (dependent on size) 2. Tracheobronchial clearance Mucous – rapid removal, but impaired by cellular injury 3. Pulmonary clearance 1. Directly trapped in fluid layer 2. Phagocytosis by macrophages and cleared in mucous. 3. Phagocytosis in alveolar macrophages and removed via lymphatic drainage. 4. Small particles directly penetrate epithelial membranes, dissolve and removed in bloodstream Distinct mechanisms matched to specific challenges; toxic consequences increase with penetration of airways, as does difficulty of removal.  Types of toxicant particle PAH = polycyclic aromatic hydrocarbons Determinants of toxic effect: 1) exposure quantity Correlation between daily mortality rate and particle concentrations during the London smog episodes (1958-1972). Schwartz & Marcus (1990) Am. J. Epidemiology 131: 185-194. Length of exposure is also critical  Determinants of toxic effect: 2) particle size Scanning electron microscopy of ultrafine (A; bar = 50 nm) and fine (B; bar = 480 nm) colloidal silica particles. Kaewamatawong T et al. Toxicol Pathol 2005;33:745-751  Size makes a BIG difference! Laminin immunohistochemistry in lungs of mice sacrificed at 24 hours after instillation with Milli-Q purified water, UFCSs or FCSs (×470). Kaewamatawong T et al. Toxicol Pathol 2005;33:745-751 staining patterns along basement membranes Control (Milli-Q purified water) Ultrafine colloidal silica particles Fine colloidal silica particles Smaller particles penetrate deep into the lungs more easily, trigger inflammation and cancer more effectively and are more difficult to remove by defences.  Combined insults can be synergistic Synergistic effects of inorganic particles and a biological compound endotoxin Mean particle size for TiO2 Ultrafine ~20 nm Fine ~250 nm Polymorphonuclear cells with phagocytic activity are markers for acute inflammatory responses  Specific toxicants Airborne agents Asbestos - causes 3 forms of lung disease – asbestosis (2 um), lung cancer (10 um) and malignant mesothelioma (5 um) (lining covering internal organs). Hazards depend on fibre length, diameter and iron content. asbestos fibres  create physical and chemical disruption of lung structure and function  Inflammatory, reactive DNA Silica – Silicosis (acute or chronic) damaging environment Naphthalene – Necrosis (tars and petroleum).  Specific toxicants Blood Borne agents Paraquat – pesticide, that induces extensive lung injury (fibrosis) when ingested. Specifically taken up by type I and II alveolar cells and interferes with electron transfer  reactive oxygen species. Monocrotaline - naturally occurring plant product (grains, honey and herbal teas). Damages specific endothelial cells lining the pulmonary vasculature, functional alteration rather than death. Causes pulmonary vasculitis and pulmonary hypertension over time (delayed lung injury). Requires metabolism in the liver prior to toxicity. Cyclophosphamide - anticancer agent. Reactive metabolites specifically target the pulmonary endothelium, creating lipid peroxidation, inflammation and pulmonary fibrosis. Interestingly, low dose cyclophosphamide used to treat paraquat pulmonary toxicity (targets and kills cells in the lungs, including those affected by paraquat, thus clearing the area to some extent).  Responses to lung injury Airway reactivity – Reflex constriction  stimulated decrease in airway diameter e.g. irritant gases, cigarette smoke Pulmonary Oedema - thickening of alveolar capillary barrier, caused by inflammation and proliferation of the tissue. - reduced exchange and compromised function - injury from histamine (allergic reaction/anaphylaxis), NO2 (creates ROS) or phosgene (chemical weapon/industrial chemical which crosslinks alveolar proteins) Fibrosis – collagen deposition active lung tissue becomes smaller and stiffer – inflammatory response (cascade IL-1b, TGFb and TNF-a) e.g. small particles – asbestos, silica, coal dust  Responses to lung injury Emphysema – abnormal enlargement of airspaces, accumulation macrophages and destruction of the walls – hyper inflated lung no longer effectively exchanges oxygen and carbon dioxide. e.g. cigarette smoke. Asthma – Narrowing of large conducting airways by inhalation of provoking agents. e.g. dust, pollen Lung cancer – Malignant tissue growth obstructs all aspects of lung function – Major cause = cigarette smoking – Also asbestos fibres and metallic dusts  Summary 4 factors determine degree of hazard associated with airborne particulates: - Type of particulate and biological effect - Concentration - Size of particle (small is usually bad) - Duration of exposure Biological effects - Systemic toxic effects - Allergy and hypersensitivity - Carcinogenesis - Irritation of mucous membranes The respiratory system has a high capacity of repair and thus copes with many toxic insults presented by the environment. Toxic responses of the renal system  Why is the kidney a target? - Large blood flow through the kidney (25% cardiac output; GFR 120 mL per minute) - Produces concentrated urine (concentrate potential toxicants) - Renal transport processes/xenobiotic processing  accumulation - Site of xenobiotic metabolism - Leaky epithelium (proximal tubule)  xenobiotic accumulation e.g. antibiotics, halogenated hydrocarbons, mycotoxins and heavy metals. Site specific differences in blood flow, transport and accumulation  vulnerable regions, specific toxic profiles  Nephrotoxicity Types of renal toxicity: Classes of nephrotoxin: 1. Direct chemical toxicity Heavy metals – Mercury – Cadmium 2. Altered haemodynamics (indirect effects  disrupted function) Halogenated hydrocarbons – Chloroform 3. pH dependent crystallisation – Bromobenzene Therapeutic agents – Aminoglycosides – Cisplatin – Amphotericin B – Cyclosporin – NSAIDs Mycotoxins – Aflatoxin  Specific sites of nephrotoxicity Glomerular injury Alter glomerular permeability to proteins e.g doxorubicin Impair glomerular ultrafiltration e.g. amphotericin B and cyclosporin.  Specific sites of nephrotoxicity Proximal tubule injury Most common site of toxicant induced renal injury Transport and accumulation e.g. aminoglycosides, β-lactam antibiotics, cisplatin and metals. Segmental differences in transport, CYP450s and β-lyase activity (bioactivation). More susceptible to ischemic injury.  Specific sites of nephrotoxicity Distal tubule injury Rare Impairment of concentrating ability and/or acidification defects e.g amphotericin B.  Nephrotoxicity examples 1. Direct chemical toxicity Cadmium interacts with the extracellular Ca2+ binding domains and E-cadherin and alters the adhesive properties of the molecule. Disrupts cadherin dependent cell-cell junctions. Cell-cell junctions and Cd disrupts adherence are vital to the structural and functional architecture of the nephron  Cadmium nephrotoxicity apoptosis adhesion molecule Toxic Cell injury death cell-cell junction e.g. Cd necrosis Sloughing of viable and non viable cells with intraluminal cell-cell adhesion Cast formation and tubular obstruction Loss of cell polarity, tight junction integrity and cell-substrate adhesion  Nephrotoxicity examples 2. Haemodynamic failure: NSAIDs NSAIDS: aspirin and ibuprofen (COX-1/2 inhibitors)  inhibition of prostaglandin synthesis.  prostaglandins are vasodilators Acute Renal Failure (large dose, reversible) – reduced renal blood flow Analgesic nephropathy (chronic, irreversible) – oxidative stress/necrosis Interstitial nephritis (inflammatory disorder/oedema (rare))  Nephrotoxicity examples 3. Crystal nephropathy Crystals form due to insolubility of compound in the urine – Reduction in intravascular volume – Renal impairment GFR (glomerular blockage) – Alterations in urine pH Examples – Antivirals (acyclovir, indinivir) – Antibacterials (sulfonamides) – Anticancer (methotrexate) Large, painful and obstructive crystals impede kidney function  Summary Kidney is sensitive to toxic insult due to its function and exposure to potentially noxious substances Site and toxin mediated specific damage related to nephron structures e.g. glomerulus, proximal tubule Common mechanisms involve: - Direct chemical insult - Haemodynamic disruption - Crystallisation The structure, function and intricacy make this a common target organ  Reading Casarett & Doull’s Toxicology – Chapter 14 Kidney – Chapter 15 Respiratory system