chitosan and plga microspheres as drug delivery ... - UniCA Eprints

1. General Introductionwhereas microbial persistence and growth in the macrophage could lead to infection in theorgan harbouring the macrophages, and hence to current infection of the blood.Macrophages are found at all epithelial lung surfaces but are far more frequent in the deeperregions of the lung (44). The number of macrophages in the lung is variable and can be raisedon exposure to certain materials, for example cigarette smoke (45, 46, 47). In the normalhuman lung, however, macrophages comprise of over 95% of the mobile cell population andaccount for 2–5% of the total alveolar cells numbering between 50 and 100 per alveolus (45,48).Macrophages are normal motile residents of the airways, interstitial matrix, and alveolarregions of the lungs (49). Particles deposited in the alveolar region are taken up rapidly bymacrophages. Phagocytic times of a few minutes (50) up to an hour (51) have been reported.The contribution of pulmonary endocytosis to the overall lung clearance is determined by theparticle size and particle shape, (52) solubility, particle burden, (53, 54) and the chemicalnature of the inhaled aerosol. Alveolar macrophage-mediated clearance is a much slowerprocess than mucociliary clearance, with retention half-times in the range of 50–80 days inrats and about 10 times longer in humans (55). Particle phagocytosis by alveolar macrophagescan be: 1) fast and efficient (titanium dioxide, diameter < 0.2 mm), 2) not efficient (ultrafineparticles), 3) incomplete (long fibers cannot be completely phagocytized by a spherical cellwith a diameter of approximately 12 mm), or 4) overloaded (ie, when particles occupy a largefraction of the volume of individual alveolar macrophages) (56). Alveolar macrophages canclear particles from the alveolar region in 4 ways: 1) transport along the alveolar surface tothe mucociliary escalator, 2) internal enzymatic degradation, 3) translocation to the tracheobronchiallymph, and/or 4) combination of the interstitial lymphatic route and mucociliarytransport. It is believed that translocation of particle-laden macrophages to the mucociliaryregion is responsible for the initial rapid clearance of insoluble particles in the first 24 hoursafter deposition (57). The enzymatic activity following phagocytosis by alveolar macrophagesis well known (58, 59) and its contribution to the overall pulmonary clearance requiresconsideration for enzyme-sensitive compounds such as biomolecules. Lung surfactant maycause large molecules to aggregate, which could enhance ingestion and digestion by alveolarmacrophages (60).15