Pulmonary clearance mechanisms

A. Impaired Pulmonary Clearance Mechanisms by Inhaled Particulates... 

The size of the fibrous particles that appear to induce disease in the animal models is compatible with the measured respiratory range in humans (Lipp-man, 1977). Most particulate deposition takes place not in the upper or conducting portion of the airways but in the alveolar region of the pulmonary tree (the respiratory unit). Some surface deposition may occur at bifurcations in the bronchial tree, but the actual amount at each location is influenced by anatomy, specific to the species—probably to an individual—as well as the variety of fiber. A large proportion of airborne particulates are rejected as part of the normal clearance mechanisms in animals, but in humans clearance mechanisms may be compromised by smoking, for example. We are unaware of any experiments on fiber toxicity using smoking rats ... 

Another issue is reproducibility. The formulation may work perfectly in an in vitro test system, but the dosage form requires aerosolization, and lung deposition is a function of the characteristics of the aerosol (dose, mass concentration, droplet/particle size, etc.) and the nature of the inspiratory maneuver, a factor that the patient has control over. These factors can influence performance to a far greater extent than can be built into a particle, and thus the term controlled does not seem a defensible objective for pulmonary delivery. The vagaries of the deposition profile and of the amount that will deposit also imply that sustaining a certain drug concentration is a difficult proposition, but the loosest definition extended release, seems an acceptable goal within the boundaries set by the clearance mechanisms. 

Correlations exist between manganese toxicity and exposure to other toxic substances in the environment, such as ozone [540-542] against which the element offers some protection against radical oxidative damage, or susceptibility to chemically induced cancer [543], cadmium [544,545], other trace elements [546], and alcohol [547]. Lysosomes in the brain have been found to play a role in manganese toxicity [548], and mechanisms for pulmonary clearance of soluble and insoluble forms of the element manganese have been discussed by Drown et al. [549]. 

Intracellular dissolution of a large variety of inhaled inorganic particles not readily soluble in the pulmonary epithelial lining fluid constitutes an important long-term clearance mechanism of the lungs. Fluorescence microscope photometry and dual laser flow cytometry of intraphagolysosomal pH in... 

Chronic Pulmonary Toxicity Chronic damage to the lungs may be due to several subsequent exposures or due to one large dose that markedly exceeds the capacity of pulmonary defense, clearance, and repair mechanisms. Chronic pulmonary toxicity includes emphysema, chronic bronchitis, asthma, lung fibrosis, and lung cancer. The single most important reason for chronic pulmonary toxicity is tobacco smoke, which induces all types of chronic pulmonary toxicity, with the exception of fibrosis. 

Several groups investigated the use of liposomes for the intra-pulmonary delivery. Farr et al. (1985) showed that the deposition of aerosolized liposomes in the human lung depends on the aerosol particle size. Short-term retention profiles for MLVs and SUVs deposited in the lung were indicative of clearance via the mucociliary transport mechanism. 

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