title: Activation of lung toll-like receptors does not exacerbate sickness responses to lipopolysaccharide in mice.
abstract: Pneumonia represents a leading cause of death. Recently, a novel treatment strategy for pneumonia has involved enhancing the host pulmonary innate immune response by pre-exposure to aerosolized toll-like receptor (TLR)9 and TLR2/6 agonists, known as O/P. O/P inhalation in mice has been demonstrated to stimulate innate lung immunity, and thus increase survival against subsequent pneumonia infection while producing barely detectable increases in systemic cytokines. Here, we examined the safety of O/P treatment when used in mice that are inflamed systemically. Swiss-Webster mice were treated with two doses of aerosolized O/P (1× or 8×) vs phosphate buffered saline (PBS) either immediately before intraperitoneal injection of 0.1mg/kg lipopolysaccharide (LPS) or PBS (equivolume) or 2h after. Sickness responses (reduced body weight, food intake, activity and social interaction) were examined at 2 and 5.5h post-treatment. Immediately following behavioral testing, mice were euthanized, perfused with PBS, and brains, spleens, livers and lungs snap frozen for assessment of pro-inflammatory cytokine mRNAs. While O/P treatment alone increased lung IL-1β, IFNγ and TNF-α, no such effects were observed in the brain, spleen or liver. Furthermore, there was no evidence that O/P treatment administered before or after LPS had any synergizing effect to potentiate the cytokine response to LPS in any compartment measured. Supportive of these findings were the measures of sickness behaviors that did not show any increased sickness response in O/P-treated mice exposed to LPS, suggestive that the cytokine signal produced in the lungs from O/P inhalation did not propagate to the brain and synergize with LPS-induced neuroinflammation. These findings support the safety of the use of O/P inhalation as a preventative measure against pneumonia and demonstrate a unique ability of the lungs to compartmentalize pulmonary inflammation and limit propagation of the cytokine signal to the brain.
authors.affiliation: Department of Symptom Research, Laboratory of Neuroimmunology of Cancer-Related Symptoms (NICRS), Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: akwalker@mdanderson.org.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Walker
authors.affiliation: Department of Symptom Research, Laboratory of Neuroimmunology of Cancer-Related Symptoms (NICRS), Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hsieh
authors.affiliation: Department of Symptom Research, Laboratory of Neuroimmunology of Cancer-Related Symptoms (NICRS), Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Luu
authors.affiliation: Department of Symptom Research, Laboratory of Neuroimmunology of Cancer-Related Symptoms (NICRS), Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Aiat A
authors.initials: AA
authors.lastname: Radwan
authors.affiliation: Department of Pulmonary Medicine, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gabriella R
authors.initials: GR
authors.lastname: Valverde
authors.affiliation: Department of Pulmonary Medicine, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Burton F
authors.initials: BF
authors.lastname: Dickey
authors.affiliation: Department of Pulmonary Medicine, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tuvim
authors.affiliation: Department of Symptom Research, Laboratory of Neuroimmunology of Cancer-Related Symptoms (NICRS), Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D055809:Illness Behavior / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology*; D051379:Mice; D011014:Pneumonia / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors
keywords: Cytokines; Innate immunity; Pneumonia; Systemic lipopolysaccharide; Toll-like receptor