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Lung Inflammation Induced by Lipoteichoic Acid or Lipopolysaccharide in Humans

¹ Center for Infection and Immunity Amsterdam (CINIMA), ² Center of Experimental and Molecular Medicine, ³ Department of Pulmonology, and ⁴ Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; ⁵ Schering-Plough Research Institute, Kenilworth, New Jersey; and ⁶ Department of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany

Correspondence and requests for reprints should be addressed to J. J. Hoogerwerf, M.D., Academic Medical Center, Center for Experimental and Molecular Medicine, Meibergdreef 9, Room G2-130, 1105 AZ Amsterdam, The Netherlands. E-mail: j.j.hoogerwerf{at}amc.uva.nl

Rationale: Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is considered to be important for an appropriate immune response against pathogens that enter the lower airways.

Objectives: We studied the effects of two different TLR agonists relevant for respiratory infections in the human lung: lipoteichoic acid (LTA; TLR2 agonist, component of gram-positive bacteria) and lipopolysaccharide (LPS; TLR4-agonist, component of gram-negative bacteria).

Methods: Fifteen healthy subjects were given LPS or LTA: by bronchoscope, sterile saline was instilled into a lung segment followed by instillation of LTA or LPS into the contralateral lung. After 6 hours, a bronchoalveolar lavage was performed and inflammatory parameters were determined. Isolated RNA from purified alveolar macrophages was analyzed by multiplex ligation–dependent probe amplification. In addition, spontaneous cytokine release by alveolar macrophages was measured.

Measurements and Main Results: Marked differences were detected between LTA- and LPS-induced lung inflammation. Whereas both elicited neutrophil recruitment, only LPS instillation was associated with activation of neutrophils (CD11b surface expression, degranulation product levels) and consistent rises of chemo-/cytokine levels. Moreover, LPS but not LTA activated alveolar macrophages, as reflected by enhanced expression of 10 different mRNAs encoding proinflammatory mediators and increased spontaneous cytokine release upon incubation ex vivo. Remarkably, only LTA induced C5a release.

Conclusions: This is the first study to report the in vivo effects of LTA in men and to compare inflammation induced by LTA and LPS in the human lung. Our data suggest that stimulation of TLR2 or TLR4 results in differential pulmonary inflammation, which may be of relevance for understanding pathogenic mechanisms at play during gram-positive and gram-negative respiratory tract infection.

Key Words: gram-positive bacteria • pneumonia • Toll-like receptor agonists

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Lipoteichoic acid (LTA) is a pathogen-associated molecular pattern displayed on the surface of gram-positive bacteria and has been shown to induce inflammatory responses in the lung in mice. The effects of LTA in human lungs have not been studied. What This Study Adds to the Field This study shows that LTA, acting via TLR2, and LPS, acting via TLR4, produce different inflammatory responses in the lung.