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Acute phase response impairs host defense against Pseudomonas aeruginosa pneumonia in mice*

Renckens, Rosemarijn MD, PhD; van Westerloo, David J. MD, PhD; Roelofs, Joris J. T. H. MD, PhD; Pater, Jennie M.; Schultz, Marcus J. MD, PhD; Florquin, Sandrine MD, PhD; van der Poll, Tom MD, PhD

doi: 10.1097/01.CCM.0B013E3181620652
Laboratory Investigations

Objective: Pseudomonas aeruginosa is a common pathogen in hospital-acquired pneumonia. Especially trauma and postsurgical patients display a profound acute phase protein response and are susceptible to acquiring pneumonia. The objective was to study the influence of the acute phase response induced by sterile tissue injury on pulmonary host defense.

Design: Laboratory investigation.

Setting: Academic medical center.

Subjects: Female C57Bl/6 wild-type mice, 8–10 wks old.

Interventions: Mice were injected subcutaneously with either turpentine or sterile saline (control) in both hind limbs 1 day before intranasal infection with P. aeruginosa.

Measurements and Main Results: The turpentine-induced acute phase response was associated with 100% lethality after induction of pneumonia, whereas control mice all survived the Pseudomonas infection. In addition, turpentine-injected mice demonstrated much higher bacterial loads in their lungs and an increased dissemination of the infection. The acute phase reaction attenuated lung inflammation during pneumonia, as reflected by histopathology, reduced pulmonary levels of proinflammatory cytokines, and a strongly diminished recruitment of neutrophils to the site of infection. Blood neutrophils harvested from turpentine injected mice displayed a reduced capacity to up-regulate their CD11b/CD18 expression upon stimulation with Pseudomonas ex vivo and during Pseudomonas pneumonia in vivo. Administration of a blocking anti-CD11b antibody to turpentine-injected and control mice almost completely abrogated the difference in bacterial outgrowth, whereas inhibition of the sympathetic nervous system did not affect the impaired pulmonary host defense in mice with an acute phase response.

Conclusions: These data suggest that a systemic acute phase response might impair host defense against P. aeruginosa pneumonia, possibly in part by inhibition of CD11b/CD18-dependent neutrophil recruitment.

From the Center for Infection and Immunity Amsterdam (CINIMA) (RR, DJvW, JMP, MJS, TvdP), Center for Experimental and Molecular Medicine (RR, DJvW, JMP, TvdP), Department of Pathology (JJTHR, SF), and Department of Intensive Care (MJS), Academic Medical Center, University of Amsterdam, The Netherlands.

Supported, in part, by grant 2001B114 from The Netherlands Heart Foundation.

The authors have not disclosed any potential conflicts of interest.

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© 2008 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins