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(Chest. 2000;117:267S.)
© 2000 American College of Chest Physicians

Response of Human Airway Epithelium In Vitro to Inflammatory Mediators*

Dependence on the State of Cellular Differentiation

Linda D. Martin, PhD; Derek Norford, DVM, PhD; Judith Voynow, MD and Kenneth B. Adler, PhD

* From the North Carolina State University (Drs. Martin and Adler), the National Institute of Environmental Health Sciences (Dr. Norford), Research Triangle Park, NC; and Duke University (Dr. Voynow), Durham, NC.

Correspondence to: Linda D. Martin, PhD, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough St, Raleigh, NC 27606


   Introduction
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 Introduction
 
Abbreviations: HNE = human neutrophil elastase; IL = interleukin; mRNA = messenger RNA; NHBE = normal human bronchial epithelial; NOS = nitric oxide synthase

Airways in patients with COPD or chronic bronchitis contain regions of damaged and regenerating epithelium intermixed with normally differentiated mucociliary areas. Responses of these different regions to the inflammatory milieu present in airways of these individuals may differ, thereby altering further development of additional lesions in the airways. In the studies reported here, we utilized normal human bronchial epithelial (NHBE) cells cultured in an air/liquid interface system as a model of well-differentiated epithelium, and the same cells cultured on plastic and submerged in medium as a model of poorly differentiated, regenerating epithelium. We investigated the responses of these different cell types to inflammatory mediators present in inflamed airways: the cytokine interleukin (IL)-13, human neutrophil elastase (HNE), and "cytomix" (10 ng/mL tumor necrosis factor-{alpha}, interferon-{gamma}, and IL-1ß). Acute exposure to IL-13 (10 ng/mL, 24 h) caused an increase in steady-state messenger RNA (mRNA) for mucin (MUC5AC) in undifferentiated cells, but did not affect MUC5AC expression in differentiated cells. Secretion of mucin and the secondary cytokine, IL-6, were both decreased in differentiated epithelial cell cultures after exposure to IL-13, but no secretory change was observed in undifferentiated cells. By contrast, chronic exposure to IL-13 (10 ng/mL, 8 days) caused an increase in mucin secretion in differentiated airway epithelial cells, and a decrease in undifferentiated cells. In response to HNE, well-differentiated cells increased steady-state levels of MUC5AC mRNA, but undifferentiated cells increased mRNA levels of another mucin gene, MUC4. Finally, the message level of inducible nitric oxide synthase (NOS) was increased by cytomix only in differentiated NHBE cultures. Undifferentiated cells did not express inducible NOS at all, but rather the constitutive forms of NOS, endothelial NOS and brain NOS. These data suggest that the response of the airway epithelium to inflammatory mediators may be markedly different in undifferentiated vs fully differentiated cells, and these responses may play a role in further exacerbation of airway inflammation. In vitro studies utilizing cultured airway epithelial cells must take the state of differentiation of these cells into account when analyzing such responses and extrapolating to the in vivo situation.


   Footnotes
 
Supported by National Instutites of Health grants HL 36982 and HL 09689.




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