Pneumotoxicology Flashcards
overview of the neuronal and muscular skeletal regulation of the airways
as contraction of the diaphram causes ventilation any drugs that act on the NMJ can have dramatic effect. ACh (+ AChEIs) also mediates bronchoconstriction
drugs that affect the respiratory centre in the brain also can have major effects on breathing (opioids + anaesthetics
sensory nerves release substance P and CGRP as a warning + defence (coughing + sneezing) for noxious stimuli. these nerves have TRP channels on them.
adrenoceptors innervated by sympathetic nerves for bronchodilator
immunology and microbiome of lungs
a major reservoir of immune cells (macrophages, neutrophils and eosinophils) which are a major target of inflammation. they also often play roles in the toxicology of compounds
due to the access to the exterior environment, the lungs have a microbiome of bacteria fungi and viruses, which explains the immune complement.
Direct measures of lung function and biochemical biomarkers
spirometry for peak flow and vital capacity.
Can calculate the tidal volume, FEV1, FVC (forced vital capacity), breathing rate, residual volume.
Blood oxygen levels (SATS). breath tests for nitric oxide, CO, cytokines, and the pH are biomarkers.
formaldehyde presence as a biomarker for lung cancer
blood tests can show CC16 which is released from clara cells following injury.
Effects of acute vs chronic injury and example causes
acute: cholinergic, histamine, arsenic, paraquat, phosgene.
causes coughing, sneezing, bronchoconstriction, bronchitis, oedema.
chronic: isocyanates, paraquat, talc, asbestos.
causes asthma, fibrosis, cancer, raised oxidative stress.
paraquat toxicity mechanisms and treatments
A herbicide that is highly toxic to the skin, lungs, and kidneys.
causes acute respiratory distress, followed by fibrosis - which can cause death. also has similar structure to MPTP and has been seen to cause parkinsonism
due to the high concentration of polyamides in the lung, paraquat is readily taken up by sodium-dependent polyamide transporters into the lung
when in the lung it is reduced to a free radical that produces superoxide anion. the production of superoxide regenerates the free radical paraquat, which is an endless cycle of superoxide production and thus lipid peroxidation and glutathione depletion. Redox cycling.
Treated by antioxidants (NAC, Vit E+C, desferrioxamine) to reduce oxidative stress. steroids and immunosuppressants to reduce inflammation.
extracorporeal toxin removal (dialysis) to prevent kidney toxicity.
3-methyl indole toxicity mechanism
3-MI is an endogenous product of tryptophan fermentation, being produced by lactobacillus. also found in beetroot.
causes pulmonary oedema and can form DNA adducts- carcinogen.
further activated to reactive metabolites by CYP450 and COX. (aspirin can reduce toxicity, particularly in lungs where there is high [COX])
Mouldy sweet potato toxicity mechanisms
4-ipomeanol is a kidney and liver toxin. accumulates in lungs
primarily affects Clara cells causing oedema and haemorrhage.
it is activated metabolically by P450, generating a reactive di-aldehyde that depletes glutathione and binds to macromolecules.
Bleomycins mechanisms
a family of bacterial compounds that are used to treat hodgkins lymphoma.
it intercalates into DNA that binds to Fe2+ and creates ROS that lead to DNA strand breaks. causes necrosis of endothelial and alveolar type 1 cells - oedema and haemorrhage. later on causes apoptosis of alveolar type 2 cells.
it also stimulates collagen synthesis - fibrosis due to influx of immune cells and inflammation
Asbestos (and talc) mechanisms of toxicity
causes fibrosis, bronchogenic carcinoma and mesothelioma
causes damage due to the fibrous nature of asbestos, with larger fibres causing lung cancer and mesothelioma, while shorter ones only asbestosis
when the fibres are longer, the macrophages are unable to engulf them (frustrated phagocytosis), leading to the macrophage to secrete lysozyme, acid hydrolyses, and reactive oxygen metabolites. this causes the fibrosis and chronic inflammation. this is a mutagenic microenvironment.
Similar mechanisms are seen in other fibrous nanoparticles, such as cerium oxide, and its theorised with microplastics too
