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CHARACTERIZATION AND IDENTIFICATION OF ENDOGENOUS
FACTOR(S) THAT ENHANCE INSULIN TRANSPORT ACROSS PRIMARY
RAT ALVEOLAR EPITHELIAL CELL MONOLAYERS
by
Rana Bahhady
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
December 2007
Copyright 2007 Rana Bahhady
Object Description
| Title | Characterization and identification of endogenous factor(s) that enhance insulin transport across primary rat alveolar epithelial cell monolayers |
| Author | Bahhady, Rana |
| Author email | bahhady@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Thesis |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2007-07-19 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-09-17 |
| Advisor (committee chair) | Shen, Wei-Chiang |
| Advisor (committee member) |
Kim, Kwang-Jin Okamoto, Curtis T. Mircheff, Austin |
| Abstract | Pulmonary delivery of peptides and proteins has been studied for decades and the recent approval of Exubera® by the US and European markets, has made non-invasive delivery of these drug macromolecules through the lungs attainable. Despite the success of several proteins and peptides in achieving appreciable systemic bioavailability relative to other non-invasive routes of administration such as nasal and oral, the underlying mechanisms of absorption remain ambiguous. Certainly the large surface area, rich blood supply, and minimal proteolytic activity compared to the gastrointestinal tract, may explain the lung's efficiency in providing a suitable environment for drug absorption. However, it is by understanding the intricate cellular machinery provided by the alveolar epithelium (proposed site of systemic absorption), that further mechanisms of drug absorption may be unraveled. In this dissertation, we investigated the effects of conditioned medium obtained from cultured primary rat alveolar epithelial cell monolayers (CMII), and rat bronchoalveolar lavage fluid (BALF) on the transport of insulin across the alveolar epithelium. Our findings indicated that protein factor(s) present in both CMII and BALF, significantly enhanced the transport of insulin across rat alveolar epithelial cell monolayers (RAECM). The mechanism of enhancement was not due to paracellular leakage or fluid-phase endocytosis, but involved transcellular pathway(s), possibly receptor-mediated endocytosis. Upon partial purification of BALF, the factor(s) with most prominent effect for enhancing insulin transport across RAECM resided in the fraction containing high molecular weight proteins (>200 kDa). The proteins, which were identified by LC-MS/MS, belonged to the macroglobulin family. The mechanism afforded by macroglobulin partially explained the insulin transport-enhancing effect observed with BALF and CMII across RAECM suggesting that other factors may be involved.; The observation that macroglobulin may be a participating factor in enhancing insulin transport across RAECM is a novel finding, which if extended to in vivo implications, may provide an additional inference of the efficiency of inhaled therapeutics that are systemically absorbed via the lung. |
| Keyword | pulmonary drug delivery; insulin |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m815 |
| Rights | Bahhady, Rana |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Bahhady-20070917 |
| Archival file | uscthesesreloadpub_Volume32/etd-Bahhady-20070917.pdf |
Description
| Title | Page 1 |
| Full text | CHARACTERIZATION AND IDENTIFICATION OF ENDOGENOUS FACTOR(S) THAT ENHANCE INSULIN TRANSPORT ACROSS PRIMARY RAT ALVEOLAR EPITHELIAL CELL MONOLAYERS by Rana Bahhady A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHARMACEUTICAL SCIENCES) December 2007 Copyright 2007 Rana Bahhady |
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