Insulin Across Respiratory Mucosae by Aerosol Delivery

Wigley, Frederick M.; Londono, Javier H.; Wood, S. H.; Shipp, Joseph C.; Waldman, Robert H.

doi:10.2337/diab.20.8.552

Cited by 170 publications

(59 citation statements)

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“…In addition, an aerosol of a nonautologous insulin to diabetic individuals resulted in lowering of blood glucose (39), suggesting that at least some protein with a molecular mass of 5 kDa can pass from the alveolar epithelium to blood and remain functionally intact in the process.…”

Section: Methodsmentioning

confidence: 99%

Fate of aerosolized recombinant DNA-produced alpha 1-antitrypsin: use of the epithelial surface of the lower respiratory tract to administer proteins of therapeutic importance.

Hubbard

Casolaro

Mitchell

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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To evaluate the possibility of administering therapeutic proteins via the respiratory route, we administered an aerosol ofrecombinant DNA-produced human a1-antitrypsin (rAAT) to anesthetized sheep and measured levels of the protein in epithelial lining fluid (ELF), lung lymph, blood, and urine.Using a nebulizer that generated aerosol droplets with a mass median aerodynamic diameter of 2.7 psm (55% of droplets were <3 ,Am, a particle size optimal for deposition on the alveolar epithelium), in vitro studies demonstrated that the aerosolized rAAT remained intact and fully functional as an inhibitor of neutrophil elastase. When aerosolized to sheep, the 45-kDa rAAT molecule diused across the alveolar epithelium, as evidenced by its presence in lung lymph and in blood. Comparison ofELF, lymph, blood, and urine rAAT levels demonstrated that the process was concentration dependent, with highest levels in ELF and in descending concentrations with 410-fold concentration differences in each consecutive compartment, respectively. Importantly (6,7), and studies with recombinant interferon-'y, interferon-a, and granulocytemonocyte colony-stimulating factor, erythropoietin, and interleukin 2 have necessitated subcutaneous, intramuscular, or intravenous routes of administration (1-5, 9, 10).As an alternative approach to administration ofrecombinant proteins (and proteins in general, independent of the source), the present study was designed to capitalize on the enormous surface area of the lung as a potential absorptive surface through which proteins of therapeutic importance could gain access to the interstitium of the lung and plasma while remaining intact. This concept is based on the knowledge that (i) droplets of 3-,um diameter inhaled as an aerosol have the potential to reach the alveolar surface (11-14); (ii) the epithelial surface of the human lower respiratory tract is very large, typically 140 m2 in adults (15); (iii) plasma proteins as large as 100 kDa are found in the epithelial lining fluid surface of the lung, suggesting that proteins can diffuse across the capillary endothelium, the alveolar interstitium, and the alveolar epithelium (16)(17)(18)(19); and (iv) although there are no quantitative data available relating to the measurement of autologous natural or recombinant proteins from lower respiratory tract epithelial lining fluid to plasma, it is known that when solutions of heterologous proteins are instilled in the trachea of experimental animals, the protein can be subsequently detected in the pulmonary interstitium and blood (20)(21)(22).As a model to evaluate the possibility of using the lower respiratory tract to administer proteins of therapeutic interest, we have examined the pulmonary absorption of an aerosol of yeast-produced human recombinant a1-antitrypsin (rAAT), a 45-kDa single-chain polypeptide that functions as an inhibitor of neutrophil elastase (23). To evaluate the absorption of the molecule, we have used sheep, an experimental animal in which the pulmonary lymphatics can be sample...

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Section: Methodsmentioning

confidence: 99%

Fate of aerosolized recombinant DNA-produced alpha 1-antitrypsin: use of the epithelial surface of the lower respiratory tract to administer proteins of therapeutic importance.

Hubbard

Casolaro

Mitchell

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…a hormone such as insulin, a series of questions has to be addressed here, because the biological mechanisms of absorption are particularly important (table 4). These questions have also been addressed in reviews published during the last few years [3,4,5, 8, 14, 24, 65, 68, 76, 85]. …”

Section: Absorbance Of High-molecular-weight Substancesmentioning

confidence: 99%

“…These questions are of increasing interest, particularly for pulmonary physicians. One example of pulmonary drug delivery is the successful use of inhaled insulin [6, 8, 10, 11] to treat diabetes mellitus, now just before the introduction for daily use. Many other approaches have been investigated [12,13,14,15](table 2) and may be developed in the near future.…”

Section: Introductionmentioning

confidence: 99%

“…In the past few years, several reports have tried to elucidate the absorptive function of the lung to understand the mechanisms involved in the therapeutic use of drugs administered via the lung [4, 7, 8,12,13,14,15]. This paper aims to raise open questions concerning the absorption of substances via the lung.…”

Section: Introductionmentioning

confidence: 99%

“…This paper aims to raise open questions concerning the absorption of substances via the lung. It is not intended to discuss the methods of inhalation or instillation separately, because technical problems concerning the administration of drugs via the lung have been dealt with in previous reports [8,9,10,11]. Methods measuring the uptake of labeled substances to analyze the permeability of lung tissue and the different epithelial cells, i.e.…”

Section: Introductionmentioning

confidence: 99%

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