Probenecid reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia

Wonnenberg, Bodo; Tschernig, Thomas; Voss, Meike; Bischoff, Markus; Meier, Carola; Schirmer, Stephan H.; Langer, Frank; Bals, Robert; Beißwenger, Christoph

doi:10.1016/j.ijmm.2014.05.002

Cited by 31 publications

(40 citation statements)

References 21 publications

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“…Collection of BALF was performed as previously described [29]. Briefly, mice were euthanized, the tracheae were cannulated and the lungs were rinsed three times with 1 mL PBS.…”

Section: Methodsmentioning

confidence: 99%

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke

et al. 2017

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The receptor for advanced glycation endproducts (RAGE) is highly expressed in the lung but its physiological functions in this organ is still not completely understood. To determine the contribution of RAGE to physiological functions of the lung, we analyzed pulmonary mechanics and structure of wildtype and RAGE deficient (RAGE-/-) mice. RAGE deficiency spontaneously resulted in a loss of lung structure shown by an increased mean chord length, increased respiratory system compliance, decreased respiratory system elastance and increased concentrations of serum protein albumin in bronchoalveolar lavage fluids. Pulmonary expression of RAGE was mainly localized on alveolar epithelial cells and alveolar macrophages. Primary murine alveolar epithelial cells isolated from RAGE-/- mice revealed an altered differentiation and defective barrier formation under in vitro conditions. Stimulation of interferone-y (IFNy)-activated alveolar macrophages deficient for RAGE with Toll-like receptor (TLR) ligands resulted in significantly decreased release of proinflammatory cytokines and chemokines. Exposure to chronic cigarette smoke did not affect emphysema-like changes in lung parenchyma in RAGE-/- mice. Acute cigarette smoke exposure revealed a modified inflammatory response in RAGE-/- mice that was characterized by an influx of macrophages and a decreased keratinocyte-derived chemokine (KC) release. Our data suggest that RAGE regulates the differentiation of alveolar epithelial cells and impacts on the development and maintenance of pulmonary structure. In cigarette smoke-induced lung pathology, RAGE mediates inflammation that contributes to lung damage.

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“…Collection of BALF was performed as previously described [29]. Briefly, mice were euthanized, the tracheae were cannulated and the lungs were rinsed three times with 1 mL PBS.…”

Section: Methodsmentioning

confidence: 99%

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke

et al. 2017

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“…In the lung infection model (59,60), anesthetized mice were infected intranasally with 2.5 ϫ 10 8 or 1 ϫ 10 8 CFU of S. aureus. At 24 h postinfection, the animals were sacrificed, and a bronchoalveolar lavage (BAL) was performed before removal of the entire lung.…”

Section: Methodsmentioning

confidence: 99%

RpiRc Is a Pleiotropic Effector of Virulence Determinant Synthesis and Attenuates Pathogenicity in Staphylococcus aureus

et al. 2016

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fIn Staphylococcus aureus, metabolism is intimately linked with virulence determinant biosynthesis, and several metabolite-responsive regulators have been reported to mediate this linkage. S. aureus possesses at least three members of the RpiR family of transcriptional regulators. Of the three RpiR homologs, RpiRc is a potential regulator of the pentose phosphate pathway, which also regulates RNAIII levels. RNAIII is the regulatory RNA of the agr quorum-sensing system that controls virulence determinant synthesis. The effect of RpiRc on RNAIII likely involves other regulators, as the regulators that bind the RNAIII promoter have been intensely studied. To determine which regulators might bridge the gap between RpiRc and RNAIII, sarA, sigB, mgrA, and acnA mutations were introduced into an rpiRc mutant background, and the effects on RNAIII were determined. Additionally, phenotypic and genotypic differences were examined in the single and double mutant strains, and the virulence of select strains was examined using two different murine infection models. The data suggest that RpiRc affects RNAIII transcription and the synthesis of virulence determinants in concert with B , SarA, and the bacterial metabolic status to negatively affect virulence. Staphylococcus aureus is a major human pathogen causing a diverse range of infections, from superficial skin and wound infections to life-threatening diseases such as bacteremia, endocarditis, osteomyelitis, deep tissue abscesses, or pneumonia (1). The pathogenicity of S. aureus is due in part to its ability to produce a large number of virulence determinants, including secreted proteins (e.g., toxins and proteases), cell wall-associated proteins (e.g., protein A and fibronectin binding proteins), and extracellular polysaccharides (i.e., capsule and polysaccharide intercellular adhesion). During colonization and infection of a host, S. aureus must adapt to rapidly changing environmental and nutritional conditions by coordinating the transcription and translation of physiologic and virulence genes (2). To coordinately control these cellular processes, S. aureus has evolved or acquired a network of regulators such as the recently identified family of proteins, RpiR, that affect pentose phosphate pathway activity and virulence determinant synthesis (3).Central to the regulatory network is the accessory gene regulator (Agr) system, a regulator of virulence determinant synthesis that responds to the bacterial population density (4). The agr locus consists of two divergent transcriptional units, RNAII and RNAIII, driven by the P2 and P3 promoters, respectively. RNAII comprises the agrBDCA operon, of which the agrBD gene products are involved in the synthesis, transport, and maturation of an autoinducing peptide (AIP). As the cell density increases, AIP accumulates in the extracellular milieu and when a threshold is achieved the two-component system AgrCA responds by activating transcription of both P2 and P3 promoters. The P3 promoter drives transcription of RNAIII, which is the re...

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“…Macrophages, neutrophils, and lymphocytes were differentiated by light microscopy. P. aeruginosa CFU values were determined by spreading appropriate dilutions of lung homogenates on agar plates (37). Lungs not subjected to BAL were fixed by instillation of PBS-buffered 4% formalin under a constant hydrostatic pressure of 30 cm for 15 min and placed in PBS-buffered 4% formalin for 24 h. The fixed lungs were embedded in 1% agarose and cut into regular slices of exactly the same thickness and embedded in paraffin (32).…”

Section: Methodsmentioning

confidence: 99%

IL-17A-mediated expression of epithelial IL-17C promotes inflammation during acutePseudomonas aeruginosapneumonia

Wolf

Sapich

Honecker

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lung epithelial cells are suggested to promote pathogen-induced pulmonary inflammation by the release of chemokines, resulting in enhanced recruitment of circulating leukocytes. Recent studies have shown that the interleukin-17C (IL-17C) regulates innate immune functions of epithelial cells in an autocrine manner. The aim of this study was to investigate the contribution of IL-17C to pulmonary inflammation in a mouse model of acute Pseudomonas aeruginosa pneumonia. Infection with P. aeruginosa resulted in an increased expression of IL-17C in lung tissue of wild-type mice. Numbers of neutrophils and the expression of the neutrophil-recruiting chemokines keratinocyte-derived chemokine and macrophage inflammatory protein 2 were significantly decreased in lungs of IL-17C-deficient (IL-17C) mice infected with P. aeruginosa at 24 h. Systemic concentrations of interleukin-6 (IL-6) were significantly decreased in infected IL-17C mice at 24 h and the survival of IL-17C mice was significantly increased at 48 h. The expression of IL-17C was reduced in infected mice deficient for interleukin-17A (IL-17A), whereas pulmonary concentrations of IL-17A were not affected by the deficiency for IL-17C. Stimulation of primary alveolar epithelial cells with IL-17A resulted in a significantly increased expression of IL-17C in vitro. Our data suggest that IL-17A-mediated expression of epithelial IL-17C amplifies the release of chemokines by epithelial cells and thereby contributes to the recruitment of neutrophils and systemic inflammation during acute P. aeruginosa pneumonia.

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Probenecid reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia

Cited by 31 publications

References 21 publications

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke

RpiRc Is a Pleiotropic Effector of Virulence Determinant Synthesis and Attenuates Pathogenicity in Staphylococcus aureus

IL-17A-mediated expression of epithelial IL-17C promotes inflammation during acutePseudomonas aeruginosapneumonia

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