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

Abstract

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-1 beta 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.

Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury

“…FACS-sorted Aoah -/- lung epithelial cells also had higher KC mRNA expression than did Aoah +/+ epithelial cells (Fig 5H). It has been shown that, distinct from macrophages form other sites, AMs that have been exposed to LPS in vivo are resistant to endotoxin tolerance or even increase their innate responsiveness [35–37]. To confirm that AMs maintain their responsiveness, 7 days after PBS or LPS instillation i.n., we explanted AMs and stimulated them with a low dose (100 pg/ml) of LPS.…”

“…Distinct from peritoneal macrophages, however, upon exposure to LPS in vivo , AMs do not become tolerant [35,36]. Instead, they respond to repeated LPS exposure by maintaining or even increasing their responsiveness [37,48]; they are able to produce chemoattractants and cytokines in the presence of persistent LPS (Fig 5), thus delaying clearance of neutrophils and prolonging inflammation. For these cells (and presumably for other LPS-responsive cells that do not develop tolerance), MAMP inactivation is especially important to terminate inflammatory responses and prevent tissue injury.…”

Lung cell-specific modulation of LPS-induced TLR4 receptor and adaptor localization

“…The combined data demonstrate that constitutive TLR4 expression in freshly isolated primary human alveolar macrophages is low, but quickly and transiently upregulated at the gene and protein level by LPS in vitro. Inhalation of LPS by healthy humans decreases TLR4 mRNA expression in alveolar macrophages after 6 h, 59 whereas lung subsegmental instillation of LPS in healthy humans does not influence the cell surface expression of TLR4 or CD14 on alveolar macrophages recovered after the same time, 60 suggesting that LPS application procedures in humans differentially affect TLR4 abundancy in alveolar macrophages.…”

The Effect of Particle Deposition on Immunological Response as Measured by Cytokine Production

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