Pharmacokinetics and Pharmacodynamics of Drugs Delivered to the Lung
Anthony J. Hickey, Sandro R.P. da Rocha in Pharmaceutical Inhalation Aerosol Technology, 2019
Different user options for the dissolution rate kinetics are available, like the traditional Noyes-Whitney equation, which depends on the water diffusion coefficient, particle size, shape, and density, as well as solubility of the drug at pH of 6.9 (physiological mucus pH) (Chaudhuri and Lukacova 2010). The absorption rate is defined by passive diffusion, following a concentration gradient, and carrier mediated transport on the apical side. Mucociliary clearance is described as a first-order process with a constant ciliary motion, and metabolism degrades inhaled particles from the respiratory epithelium (Bäckman et al. 2017a). Published human lung physiological parameters, like surface area, thickness, and volume for the mucus and cells were incorporated into this model.
Methods for the Morphological Study of Tracheal and Bronchial Glands
Joan Gil in Models of Lung Disease, 2020
By the coordination of ciliary movement, airway mucus secretion plays a primary role in mucociliary clearance and thus in the defense mechanisms against inhaled particles and pathogens as well as reflexes (bronchoconstriction and cough) and local immune responses. Secretory cells exist at the airways both in the surface epithelium that contains mucuous cells (goblet cells), serous cells, and Clara cells, and in the submucosal glands, which consist of serous and mucous cells. The epithelial serous cell has only recently been found in human and rat, and in human it is frequently found during the fetal stage and little is known of its fate postnatally. It resembles the serous cell of the human and rat submucosal gland, and, compared to the surface mucous cell (goblet cell), it is very rare. Clara cells are found only in the terminal bronchiolus of many species, including humans, and the nature of their secretion is still obscure. In healthy adult humans the volume of the submucosal glands down to the fifth generation in bronchi was calculated to be as much as 4 ml and submucosal glad cells, in volume, exceed the surface mucous cells (goblet cells) by a ratio of about 40:1 (Reid, 1960). Furthermore, autonomic nerves do not regulate secretion from surface goblet cells; the submucosal glands probably make the greater contribution to the production of respiratory tract mucus in human lungs.
Bronchus-associated lymphoid tissue and immune-mediated respiratory diseases
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
From the outer part of the nose to the respiratory bronchioles immediately distal to the trachea and bronchi, the airway mucosa is covered by a pseudostratified ciliated epithelium that is interspersed with goblet cells producing mucus that covers the cilia. Large numbers of exocrine glands are present in the underlying mucosa, which together with goblet cells produce mucus that covers the epithelial surface. The glands are surrounded by plasma cells that produce predominantly dimeric IgA, which is translocated from the basolateral to the luminal side of the epithelium by the polymeric immunoglobulin receptor. Secretory IgA, present in the mucus layer, participates in immune defense by neutralizing microbial toxins and pathogens and by preventing commensal bacteria from breaching the mucosal surface. The mucosal secretions of NALT and conducting systems of the upper airway also contain significant quantities of IgG that are transported by the neonatal Fc receptor (FcRn) expressed by the epithelium. The mucus and its content are constantly translocated upward by the ciliated cells, which provide mechanisms for mucociliary clearance of inhaled antigens, including antigens complexed with immunoglobulins. The adequate functioning of these cilia and the mucociliary escalator is critical in lung defense, and people who have primary ciliary dyskinesia (PCD) or cystic fibrosis frequently have infections with Pseudomonas or Staphylococci.
Developments in the discovery and design of intranasal antidepressants
Published in Expert Opinion on Drug Discovery, 2020
Małgorzata Panek, Paweł Kawalec, Andrzej Pilc, Władysław Lasoń
The transport of particular molecules from the nose to the brain may be restricted by an enzymatic barrier, mucociliary clearance, protective barriers, and low bioavailability. Cytochrome P450–dependent monooxygenase, carboxyl esterase, and aminopeptidase are examples of enzymes present in the nasal mucosa. They may decrease the transport of various proteins or peptides across the nasal membrane. They also create a pseudo-first-pass effect because the transported molecules undergo enzymatic degradation in the nasal cavity or nasal epithelium. Mucociliary clearance is a self-clearing mechanism that is responsible for the rapid removal from the body of particles caught from the nasal mucosa. It is considered to be a protective temporal barrier that limits the absorption of drug across the nasal epithelium. To overcome this barrier, some bioadhesive materials are added to drug formulations. Another protective barrier is the physical barrier of the nasal membrane. The low bioavailability of drugs is a considerable problem. This applies in particular to polar drugs with a large molecular size. While lipophilic drugs have a bioavailability of almost 100%, the bioavailability of polar substances is estimated at about 10%. To improve the permeability of polar drugs, an absorption enhancer could be added to drug formulation [20].
Effects of hepatocyte growth factor-transfected mesenchymal stem cell transplantation in canine injured vocal folds
Published in Growth Factors, 2023
Xingqiao Xie, Xumao Li, Xinsheng Lin, Xiangyu Chen, Chenshan Zhang, Guangbin Sun
The VFs are continually exposed to inhaled pathogens, toxins, and foreign particles. Mucociliary clearance is an essential part of the defense system, which relies on appropriate interactions between the ciliated epithelium, the height of the periciliary fluid, and mucus. Mucus traps inhaled pathogens and particles, while cilia move both the mucus layer and fluid in the underlying periciliary layer (Kahwa, Balemba, and Assey 2000; Stannard and O'Callaghan 2006). Scanning electron microscopy revealed that the HGF-transfected ADSCs group had fewer microvilli with a slightly sparse distribution than normal VFs, whereas these negative changes were more severe in other groups. Densely packed and extensively distributed microvilli can protect VFs from foreign factors, participating in VF repair.
Epithelial damage in the cystic fibrosis lung: the role of host and microbial factors
Published in Expert Review of Respiratory Medicine, 2022
Arlene M. A. Glasgow, Catherine M. Greene
The epithelium of the conducting airways is lined by the ~10 μm deep ASL, which consists of two layers of differing chemical composition. The watery periciliary layer (PCL) sits on top of the epithelial cells, bathing the cilia whilst allowing them to beat. The mucus layer overlays the PCL, sits on the tips of the cilia, and has a more gel-like consistency due to the presence of large glycosylated proteins called mucins. The two main airway mucins are MUC5AC and MUC5B, which are secreted by the goblet epithelial cells and submucosal glands, respectively [2]. The mucus layer serves as a trap for debris and pathogens, which are subsequently removed from the lung via mucociliary clearance – the co-ordinated beating of the cilia to propel mucus upwards along the respiratory tract and out of the airway. This so-called mucociliary escalator is an essential component of pulmonary innate defense, therefore the regulation of ASL hydration and ionic composition is key to protecting the lung from infectious and environmental insults.