Epithelium surfactant

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

In another approach, Parnigotto and coworkers reconstructed corneal structures in vitro by using corneal stroma containing keratocytes to which corneal epithelial cells from bovine primary cultures were overlaid [73], However, this particular corneal model did not contain an endothelial layer. This model was histochemically characterized and the toxicity of different surfactants was tested using MTT methods. This stroma-epithelium model has been reported to show a cornea-like morphology, where a multilayered epithelial barrier composed of basal cells (of a cuboidal shape) and superficial cells (of a flattened shape) is noted. Furthermore, the formation of a basement membrane equivalent and expression of the 64-kDa keratin were reported, indicating the presence of differentiated epithelial cells. The toxicity data for various surfactants obtained with this model correlate well with those seen by the Draize test [73], However, this corneal equivalent was not further validated or used as a model for permeation studies. 

Parnigotto PP, Bassani V, Montesi F, Conconi MT. Bovine comeal stroma and epithelium reconstructed in vitro Characterisation and response to surfactants. Eye 12 304-310(1998). 

The situation is, however, different in the alveolar region of the lung where the respiratory gas exchange takes place. Its thin squamous epithelium is covered by the so-called alveolar surface liquid (ASL). Its outermost surface is covered by a mixture of phospholipids and proteins with a low surface tension, also often referred to as lung surfactant. For this surfactant layer only, Scarpelli et al. [74] reported a thickness between 7 and 70 nm in the human lung. For the thickness of an additional water layer in between the apical surface of alveolar epithelial cells and the surfactant film no conclusive data are available. Hence, the total thickness of the complete ASL layer is actually unknown, but is certainly thinner than 1 gm. 

Ectopeptidases of the alveolar epithelium are also involved in the regulation of pulmonary surfactants [24], The cell-surface enzymes on monocyte-... 

The alveolar epithelium consists of so-called Type I and Type II cells. Type I cells cover over 90% of the alveolar surface, have a large surface, and are thin. Type II cells are larger in numbers but are small. Therefore, they cover only about 7% of the surface of the alveoli. Type II cells produce the phospholipids that make up the surfactant layer. 

Paraquat is commonly combined in commercial herbicides with diquat, a related compound in several instances, the commercial preparations splashed in the eyes have caused serious injury. " Effects have been loss of corneal and conjunctival epithelium, mild iritis, and residual corneal scarring. In contrast, in the eye of a rabbit, one drop of a 50% aqueous solution of pure paraquat caused slow development of mild conjunctival inflammation and pure diquat proved even less irritating. Presumably, the surfactants present in the commercial preparations are responsible for the severe eye injuries to humans. ... 

Liposomes were formed from 1,2-dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Choi) and the effect of liposomal entrapment on pulmonary absorption of insulin was related to oligomerization of insulin (Liu et al. 1993). Instillation of both dimeric and hexameric insulin produced equivalent duration of hypoglycemic response. However, the initial response from the hexameric form was slightly slower than that from dimeric insulin, probably due to lower permeability across alveolar epithelium of the hexameric form caused by larger molecular size. The intratracheal administration of liposomal insulin enhanced pulmonary absorption and resulted in an absolute bioavailability of 30.3%. Nevertheless, a similar extent of absorption and hypoglycemic effects was obtained from a physical mixture of insulin and blank liposomes and from liposomal insulin. This suggests a specific interaction of the phospholipid with the surfactant layer or even with the alveolar membrane. 

The most efficient rectal absorption enhancers, which have been studied, include surfactants, bile acids, sodium salicylate (NaSA), medium-chain glycerides (MCG), NaCIO, enamine derivatives, EDTA, and others [45 17]. Transport from the rectal epithelium primarily involves two routes, i.e., the paracellular route and the transcellular route. The paracellular transport mechanism implies that drugs diffuse through a space between epithelial cells. On the other hand, an uptake mechanism which depends on lipophilicity involves a typical transcellular transport route, and active transport for amino acids, carrier-mediated transport for (3-lactam antibiotics and dipeptides, and endocytosis are also involved in the transcellular transport system, but these transporters are unlikely to express in rectum (Figure 8.7). Table 8.3 summarizes the typical absorption enhancers in rectal routes. 

A weakening of the binding forces between the keratinized epithelium and the layer of grease via the reduction of the surface tension between the water and the water-resistant oil/grease. Because of this reduced surface tension, water (and surfactant molecules) can penetrate into the finest wrinkles of the skin. In this way, more and more interface is occupied by surfactant, and the adhesiveness of the soil-containing layer is further weakened, a process facilitated by mechanical rubbing. 

The pulmonary alveolar epithelium is comprised of two morphologically distinct cells, type I and type II cells. Type I cells are extremely large, squamous cells that make up 95% of the alveolar surface. Type II cells are smaller cuboidal cells that secrete and recycle surfactant and cover the remaining 5% of the alveolar surface. Mechanical distention of fetal lung tissue has been shown to stimulate expression of the type I cell phenotype and inhibit expression of the type II phenotype. Lumenal mechanical stim-... 

Penetration enhancers are substances that can increase the absorption of a co-administered dmg, and include surfactants, bile salts, chelating agents, and fatty acids. Penetration enhancers are widely used in dmg delivery to potentiate absorption across various types of epithelia, including the epithelium of the gastrointestinal tract. However, a major limiting factor in the general acceptance of absorption enhancers for improving oral dmg absorption is the non-specific nature of their effects. 

The alveolar surface represents a thin liquid film formed at the interface between the alveolar gas phase and a liquid hypophase covering the epithelium. This film is stabilised by the alveolar surfactant (AS), consisting mainly of phospholipids and proteins. AS plays an important role in alveolar stabilisation in the process of breathing. It is known that AS components exist as individual molecules and as various lipid and protein/lipid micellar structures present in the so-called hypophase and, according to some researchers, form a continuous lipid monolayer at the water/air interface [e.g. 1-4]. 

Experimentally, the macrocyclic trichothecenes satra-toxin G, isosatratoxin F, and roridin A have been shown to cause nasal and pulmonary toxicity when administered intranasally or intratracheally to mice. Intranasal exposure of satratoxin G and roridin A induced apoptosis of olfactory sensory neurons resulting in atrophy of the olfactory epithelium and olfactory nerve layer of the olfactory bulb in the frontal brain (Islam et al, 2006, 2007). Alveolar-type II cells and alveolar macrophages were injured following intratracheal instillation of isosatratoxin F or Stachybotrys spores with marked changes in surfactant synthesis and secretion (Rand et al, 2002). 

The quaternary surfactants benzalkonium chloride (BAG) and benzethonium chloride are preferred by many manu-fecturers because of their stabihty, excellent antimicrobial properties in acid formulation, and long shelf life. They exhibit toxic effects on both the tear film and the corneal epithelium and have long been known to increase drug penetration. The toxicity of these compounds may be increased by the degree of acidity of the formulation. 

---