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1 University of Zurich Medical School, Institute of Anesthesiology, Zurich, Switzerland; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
2 University of Zurich Medical School, Institute of Physiology, Zurich, Switzerland
3 University of Zurich Medical School, Institute of Anesthesiology, Zurich, Switzerland; University of Zurich Medical School, Institute of Physiology, Zurich, Switzerland
4 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
5 University of Zurich Medical School, Institute of Physiology, Cardiovascular Research, Zurich, Switzerland
6 University of Zurich Medical School, Institute of Anesthesiology, Zurich, Switzerland
* To whom correspondence should be addressed. E-mail: Beatrice_Beck.Schimmer{at}access.unizh.ch.
Respiratory epithelial cells play a crucial role in the inflammatory response in endotoxin-induced lung injury, an experimental model for acute lung injury. To determine the role of epithelial cells in the upper respiratory compartment in the inflammatory response to endotoxin, tracheobronchial epithelial cells (TBEC) were exposed to lipopolysaccharide (LPS). Expression of inflammatory mediators was analyzed and the biological implications were assessed by chemotaxis and adherence assays. Epithelial cell necrosis and apoptosis were determined to identify LPS-induced cell damage. Treatment of TBEC with LPS-induced enhanced protein expression of cytokines and chemokines (increases of 235% - 654%, p < 0.05), with increased chemotactic activity regarding neutrophil recruitment. Expression of the intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) was enhanced by 52% - 101% (p < 0.0001). This upregulation lead to increased adhesion of neutrophils, with > 95% adherence to TBEC after LPS stimulation, which could be blocked by either ICAM-1 (69%) or VCAM-1 antibodies (55%) (p < 0.05). Enhanced neutrophil-induced necrosis of TBEC was observed, when TBEC were exposed to LPS. Reduced neutrophil adherence by ICAM-1- or VCAM-1 antibodies resulted in a significant lower TBEC killing (52% and 34%, respectively, p < 0.05). Therefore tight adherence of neutrophils to TBEC appears to promote epithelial cell killing. In addition to indirect effector cell-induced TBEC death, direct LPS-induced cell damage was seen with increased apoptosis rate in LPS-stimulated TBEC (36% increase of caspase-3, p < 0.01). These data provide evidence that LPS induces TBEC killing in a necrosis- and apoptosis-dependent manner.
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