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Priming of Alveolar Macrophages upon Instillation of Lipopolysaccharide in the Human Lung

¹ Center for Infection and Immunity Amsterdam, ² Center of Experimental and Molecular Medicine, ³ Department of Pulmonology, ⁴ Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and ⁵ Department of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany

Correspondence and requests for reprints should be addressed to Jacobien J. Hoogerwerf, M.D., Academic Medical Center, Center for Experimental and Molecular Medicine, Meibergdreef 9, Room G2-132, 1105 AZ Amsterdam, The Netherlands. E-mail: j.j.hoogerwerf{at}amc.uva.nl

The airways are continuously exposed to respiratory pathogens, which may result in bacterial pneumonia, one of the most common infectious diseases and the leading cause of sepsis. Considering that recurrent exposure to microbial products can lead to tolerance of immune cells, and that this might contribute to the susceptibility to nosocomial infection, we investigated the effect of in vivo lipopolysaccharide (LPS) instillation on the responsiveness of alveolar macrophages. In eight healthy humans, sterile saline was instilled into a lung segment by bronchoscope, followed by instillation of LPS into the contralateral lung; 6 hours later, a bilateral bronchoalveolar lavage was performed, and purified alveolar macrophages were ex vivo stimulated with LPS or lipoteichoic acid (LTA), triggering Toll-like receptor (TLR)-4 and -2, respectively. In vivo LPS-exposed alveolar macrophages were primed, as reflected by increased ex vivo LPS- and LTA-induced IL-1β and IL-6 gene expression and production compared with in vivo saline-exposed alveolar macrophages. LPS instillation did not influence the surface expression of TLR4 or TLR2. Furthermore, LPS instillation did not impact on the expression of a number of extracellular and intracellular regulators of TLR signaling. However, p38 mitogen-activated protein kinase remained phosphorylated in alveolar macrophages upon LPS instillation. The current data demonstrate that LPS instillation in the human lung primes alveolar macrophages for further stimulation with either LPS or LTA, possibly by sustained p38 mitogen-activated protein kinase activation.

Key Words: alveolar macrophages • bronchial instillation • endotoxin tolerance • lipopolysaccharide • lipoteichoic acid