title: Acute cytotoxicity and apoptotic effects after l-Pam exposure in different cocultures of the proximal and distal respiratory system.
abstract: Sulphur and nitrogen mustard are strong alkylating agents which can cause after inhalation acute lung injury in the larynx, trachea and large bronchi and can lead to alveolar edema. In our study we tested the N-Lost l-Phenylalanine Mustard (l-Pam). Therefore we seeded the alveolar type II cell line NCI H441 on the upper membrane of a Transwell filter plate and the endothelial cell line ISO-Has-1 on the lower side of the membrane for the alveolar model and combined the human bronchial explant-outgrowth cells and fibroblasts in the bronchial model and exposed both models with various concentrations of l-Pam. Treatment with l-Pam led to a concentration-dependent decrease of the transepithelial electrical resistance and therefore impairment of barrier function in both models. Changes in morphology could be observed. In the bronchial model damaged cell organelles whereas in the alveolar model a widening of intercellular spaces could be seen. Loss of cell-matrix adhesion as well as apoptotic and necrotic cell death could be demonstrated. In conclusion, treatment with the nitrogen mustard in the coculture models showed comparable results to sulphur mustard treatment and thus this model could be useful to explore similarities and differences in signal transduction pathways after treatment with both sulphur and nitrogen mustard.
authors: Institute of Pathologie, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany. pohlc@uni-mainz.de
authors: Christine
authors: C
authors: Pohl
authors: Helene
authors: H
authors: Hofmann
authors: Michaela
authors: M
authors: Moisch
authors: Mirko
authors: M
authors: Papritz
authors: M
authors: M
authors: Iris Hermanns
authors: Jasmin
authors: J
authors: Dei-Anang
authors: Eckhard
authors: E
authors: Mayer
authors: Kai
authors: K
authors: Kehe
authors: Charles James
authors: CJ
authors: Kirkpatrick
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D018920:Coculture Techniques; D003603:Cytotoxins / Q000633:toxicity; D017097:Electric Impedance; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space; D008558:Melphalan / Q000633:toxicity*; D046529:Microscopy, Electron, Transmission; D015388:Organelles; D020543:Proteome / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000166:cytology; D023382:Toxicity Tests, Acute; D014617:Vacuoles
chemical_list: D003603:Cytotoxins; D020543:Proteome; D008558:Melphalan