Surfactant protein damage

Alveoli represent the primary site for gas exchange within the lung, and thus their health is vital for survival. Alveolar conditions with a primary genetic cause, such as surfactant protein-B (SP-B) deficiency and SP-C deficiency, are prime candidates for a rAAV-gene therapy approach. Diseases in which alveoli are damaged secondary to other defects might also be treated with gene transfer. Such conditions include environmental toxin exposure, infectious diseases, and adult respiratory distress syndrome (ARDS) (Table 4.1) (Rolls et al., 1997, 1998, 2001 Cheers et al 1999 Ruan et al., 2002). 

FIGURE 31.8 Protein damage potential of a number of surfactants determined using the zein dissolution test. Higher the zein dissolution, higher is the damage potential of the surfactant. 

In adults, a severe form of lung injury can develop in association with sepsis, pneumonia, and injury to the lungs due to trauma or surgery. This catastrophic disorder is known as acute respiratory distress syndrome (ARDS) and has a mortality rate of more than 40%. In ARDS, one of the major problems is a massive influx of activated neurophils which damage both vascular endothelium and alveolar epithelium and result in massive pulmonary edema and impairment of surfactant function. Neutrophil proteinases (e.g., elastase) break down surfactant proteins. A potential therapeutic strategy in ARDS involves administration of both surfactant and antiproteinases (e.g., recombinant a I -antitrypsin). 

Haddad lY, Crow JP, Hu P, Yaozu Y, Beckman J, Matalon S. Concurrent generation of nitric oxide and superoxide damages surfactant protein A. Am J Physiol... 

It could well be that many of the results of increased transport rates are determined by membrane damage, rather than by reversible physical effects when surfactants are used above their CMC. Studies on the solubilization of protein have in several cases demonstrated a remarkable parallel between solubilizing ability and membrane action (30). 

Another aspect of polysorbates is that they are inherently susceptible to oxidative degradation. Often, as raw materials, they contain sufficient quantities of peroxides to cause oxidation of protein residue side chains, especially methionine (59). The potential for oxidative damage arising from the addition of stabilizer emphasizes the point that the lowest effective concentrations of excipients should be used in formulations. For surfactants, the effective concentration for a given protein will depend on the mechanism of stabilization. It has been postulated that if the mechanism of surfactant stabilization is related to preventing surface-denaturation, the effective concentration will be around the detergent s critical micellar concentration. Conversely, if the mechanism of stabilization is associated with specific protein-detergent interactions, the effective surfactant concentration will be related to the protein concentration and the stoichiometry of the interaction (39). 

Formulation additives used in topical drug or pesticide formulations can alter the stratum comeum barrier. Surfactants are least likely to be absorbed, but they can alter the lipid pathway by fluidization and delipidization of lipids, and proteins within the keratinocytes can become denatured. This is mostly likely associated with formulations containing anionic surfactants than non-ionic surfactants. Similar effects can be observed with solvents. Solvents can partition into the intercellular lipids, thereby changing membrane lipophilicity and barrier properties in the following order ether/acetone > DMSO > ethanol > water. Higher alcohols and oils do not damage the skin, but they can act as a depot for lipophilic drugs on the skin surface. The presence of water in several of these formulations can hydrate the skin. Skin occlusion with fabric or transdermal patches, creams, and ointments can increase epidermal hydration, which can increase permeability. 

The addition of surfactants allows a modification of the kinetics of nonspecific cell adhesion to bubbles. When substances such as methyl cellulose or Pluronic F68 are added to the culture, the time needed for cell adhesion to occur is increased (Meier et al., 1999). In this way, the number of cells adhered to a bubble at the moment of its explosion is lower by several orders of magnitude. The non-ionic surfactant Pluronic F68 is so far the best option, since it efficiently protects cells from bubble damage without significantly affecting oxygen transfer. Flowever, its presence may be undesirable for certain stages of protein purification. 

The basic function of a cleanser is to promote health and hygiene of skin by removing excess dirt, sebum, and bacteria from skin and promoting exfoliation. However, as explained earlier, cleanser surfactants also interact with SC proteins and lipids, causing damage to the SC barrier, leading to a net loss in SC hydration. 

It is clear that harsh surfactants have the potential to cause immediate alteration to SC proteins and lipids, and progressively increasing degrees of damage over time that can eventually result in a barrier breakdown. The first step toward mild cleansing is to minimize the damage potential of surfactants... 

SC. Surfactant interaction with lipids and proteins leads to a fundamental breakdown of biological processes that underpin skin health. Mild surfactants have lead to cleansers with significantly reduced drying and damaging potential but only within the last decade have truly moisturizing cleansers begun to emerge. 

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