title: Gene expression profiles in alveolar macrophages induced by lipopolysaccharide in humans.
abstract: Lipopolysaccharide (LPS) is ubiquitous in the environment. Inhalation of LPS has been implicated in the pathogenesis and/or severity of several lung diseases, including pneumonia, chronic obstructive pulmonary disease and asthma. Alveolar macrophages are the main resident leukocytes exposed to inhaled antigens. To obtain insight into which innate immune pathways become activated within human alveolar macrophages upon exposure to LPS in vivo, we conducted a study in eight healthy humans, in which we instilled sterile saline into a lung segment by bronchoscope, followed by instillation of LPS into the contralateral lung. Six hours later, a bilateral bronchoalveolar lavage was performed and whole-genome transcriptional profiling was done on purified alveolar macrophages, comparing cells exposed to saline or LPS from the same individuals. LPS induced differential expression of 2,932 genes in alveolar macrophages; 1,520 genes were upregulated, whereas 1,440 genes were downregulated. A total of 26 biological functions were overrepresented in LPS-exposed macrophages; 44 canonical pathways affected by LPS were identified, among which the genes associated with the role of pattern recognition receptors in recognition of bacteria and viruses represented the top pathway. Other pathways included cellular immune response, signaling by tumor necrosis factor (receptor) family members, cytokine signaling and glucocorticoid receptor signaling. These results reveal for the first time a large number of functional pathways influenced by the biologically relevant challenge provided by LPS administered into the airways. These data can assist in identifying novel targets for therapeutic intervention in pulmonary diseases associated with LPS exposure, including pneumonia, asthma and chronic obstructive pulmonary disease.
authors.affiliation: Joint Unit Hospices Civils de Lyon - bioMérieux, Hôpital Edouard Herriot, Lyon, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Reynier
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.forename: Jacobien J
authors.initials: JJ
authors.lastname: Hoogerwerf
authors.forename: Paul
authors.initials: P
authors.lastname: Bresser
authors.forename: Jaring S
authors.initials: JS
authors.lastname: van der Zee
authors.forename: Malick
authors.initials: M
authors.lastname: Paye
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pachot
authors.forename: Bruno
authors.initials: B
authors.lastname: Mougin
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D016000:Cluster Analysis; D000074049:Cytokine TWEAK; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D000074049:Cytokine TWEAK; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047889:Receptors, Tumor Necrosis Factor, Type II; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors