Background

1. Toxic responses of the Respiratory systemFourth StageToxicology Lab.6April, 2018Assist. Lec. Amani AneesAbbody

3. Background • The respiratory system has direct contact with the inhaled air that contains a variety of environmental pollutant (e.g., gas, dust, fiber and tobacco smoke). • Particles of 1-2 micrometers are the optimal size for reaching the alveoli. • Relatively large particles get trapped in nasal hairs and never enter the lower respiratory tract, or they are removed by coughing or sneezing.

4. In the alveoli, some material may dissolve & be absorbed into the bloodstream or interstitial fluid. • Particles that do not dissolve may be phagocytized by macrophages & the phagocytic cells are either swept up the tracheobronchial tree or they migrate to the interstitial fluid. • Some insoluble particles may remain sequestered in the lung.

5. Normal Lung Sections of lung tissue have the appearance of fine lace because most of the lung is composed of thin-walled alveoli. The alveoli are composed of a single layer of squamous epithelium. This slide also contains sections across many bronchioles. Bronchioles can be recognized by the fact that they are lined by ciliated columnar epithelium (larger bronchioles) or by cuboidal epithelium (smaller bronchioles).

6. Responses of the lung to injury: • Emphysema. • Fibrosis. • Asthma • Lung cancer.

7. Emphysema The lung become larger and too compliant. Destruction of the gas –exchanging surface area result in distended, hyper-inflated lung. Impair O2 and CO2 exchange as a result of both loss of tissue and air trapping. The major cause is cigarette smoke inhalation.

10. Fibrosis Fibrotic lung contain increased amounts of collagen. Increasing type I collagen relative to type III collagen may result in a stiffer lung. Changes in collagen cross linking in fibrotic lung. Risk factor tobacco smoking, old age, male more susceptible to fibrosis.

11. Dense fibrosis and typical honeycombing aspect can be recognized.

12. Asbestosis showing the characteristic ferruginous bodies and marked interstitial fibrosis.

13. The arrow points to an uncoated segment of asbestos fiber in this ferruginous body.

14. Asthma Characterized by attack of SOB. Narrowing of bronchi and bronchioles. Increase airway reactivity of bronchial smooth muscle in response to irritants.

17. Lung cancer An activated carcinogen or its metabolites may interact with DNA. DNA damage caused by active oxygen species. Ionizing radiation lead to formation of superoxide. cigarette smoke contains high quantities of active oxygen species

19. Mechanisms of toxicants that cause pulmonary injury:Pulmonary toxicity secondary to drugs or toxicants may be due to a variety of mechanisms, which are as follows: 1. Cytotoxic pulmonary injury. 2. Deposition of phospholipids within cells. 3. Pulmonary vascular damage. 4-Central nervous system (CNS) injury5. Immune system–mediated injury.

20. 1-Cytotoxic pulmonary injury: • Multiple mechanisms may be responsible for cytotoxic pulmonary injury due to drugs, including: • reactive oxygen species (ROS) e.g. nitrofurantoin & methotrexate (MTX), & bleomycine • 2. impairment of alveolar repair mechanisms . • 3. release of various cytokines.

21. 2-Deposition of phospholipids within cells: Amiodarone has been demonstrated to produce phospholipidosis in alveolar macrophages & in type 2 cells. The process is reversible with discontinuation of the drug.

22. Pathologic manifestation associated with Amiodarone induced pulmonary toxicity. Black arrow demonstrates representative lipid laden macrophage.

23. 3-Drug-induced pulmonary vascular disease clinically manifested as: acute pulmonary edema. pulmonary vascular occlusion. pulmonary hypertension or hemorrhage.

24. Drugs causing pulmonary vascular disease: • Oral contraceptives: estrogens are well known to increase platelet adhesiveness and decrease venous tone and can cause a procoagulant effect. • Pulmonary vasculitisis caused by several drugs, including nitrofurantoin, sulfonamides, penicillins & phenytoin. • Several anticoagulants, penicillamine, amiodarone, cocaine, hydralazine, nitrofurantoin, MTX, carbamazepine are recognized to produce diffuse alveolar hemorrhage. • Acute pulmonary edema: Salicylate and Overdose of heroin

25. Pulmonary hemorrhage in which alveolar spaces are filled with red blood cells.

26. Pulmonary Edema Normal x-ray

27. 4-Central nervous system injury: • Neurogenic pulmonary edema (NPE) is a relatively rare characterized by an increase in pulmonary interstitial and alveolar fluid. • Neurogenic pulmonary edema develops within a few hours after a neurologic insult. • Neurological insults include: subarachnoid hemorrhage, traumatic brain injury, intracerebral hemorrhage, meningitis, spinal cord injury, intracranial tumors & ischemic stroke.

28. 5-Immune system–mediated injury: • Drugs can act as potential antigens induce an immune cascade that can lead to immune-mediated lung toxicity. • Deposition of antigen-antibody complexes may trigger an inflammatory response, leading to interstitial lung disease. • Drug-induced systemic lupus erythematosus is an example of immune-mediated lung damage. • e.g., hydralazine, procainamide

29. Thanks for Listening