Transgenic Cystic Fibrosis Mice Exhibit Reduced Early Clearance of <i>Pseudomonas aeruginosa</i> from the Respiratory Tract

Schroeder, Tobias; Reiniger, Nina; Meluleni, Gloria; Grout, Martha; Coleman, Fadie T.; Pier, Gerald B.

doi:10.4049/jimmunol.166.12.7410

Cited by 100 publications

(110 citation statements)

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“…Further studies suggested that internalisation of P. aeruginosa is also mediated by other mechanisms. The uptake mechanisms also seem to depend on the bacterial strain, since rough, mucoid strains of P. aeruginosa are able to enter epithelial cells independently of CFTR expression [14]. …”

Section: Inflammation In Cystic Fibrosismentioning

confidence: 99%

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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Sphingolipids and in particular ceramide have been shown to be critically involved in the response to many receptor-mediated, but also receptor-independent, mainly stress stimuli. Recent studies demonstrate that ceramide plays an important role in the pathogenesis of cystic fibrosis, a hereditary metabolic disorder caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator. Patients with cystic fibrosis suffer from chronic pulmonary inflammation and microbial lung infections, in particular with Pseudomonas aeruginosa. Chronic pulmonary inflammation in these patients seems to be the initial pathophysiological event. Inflammation may finally result in the high infection susceptibility of these patients, fibrosis and loss of lung function. Recent studies demonstrated that ceramide accumulates in lungs of cystic fibrosis mice and causes age-dependent pulmonary inflammation as indicated by accumulation of neutrophils and macrophages in the lung and increased pulmonary concentrations of Interleukins 1 and 8, death of bronchial epithelial cells, deposition of DNA in bronchi and high susceptibility to Pseudomonas aeruginosa infections. Genetic or pharmacological inhibition of the acid sphingomyelinase blocks excessive ceramide production in lungs of cystic fibrosis mice and corrects pathological lung findings. First clinical studies confirm that inhibition of the acid sphingomyelinase with small molecules might be a novel strategy to treat patients with cystic fibrosis.

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Section: Inflammation In Cystic Fibrosismentioning

confidence: 99%

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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Section: Pseudomonas Aeruginosa In Cystic Fibrosismentioning

confidence: 99%

“…To wit, results showing that WT-CFTR is a receptor for P. aeruginosa that mediates effective innate immunity and that this receptor is not functional in CF [9,10] are the ones most consistent with clinical and experimental observations. One curious additional observation about this interaction has also been reported: the mucoid strains of P. aeruginosa responsible for chronic infection lose the bacterial ligand for CFTR [8,11,12], indicating that the P. aeruginosa-CFTR direct interaction is likely to be primarily of relevance to the early stages of infection, whereas in the later stages of infection other properties of the bacterium and the CF host conspire to allow for maintenance of the chronic infectious state.However, there are clearly investigators who hypothesize that the major role of the airway epithelium in susceptibility to P. aeruginosa lung infection is through defects in ion transport, leading to dehydrated airway surface layer (ASL) and thickened mucus that cannot be cleared by the ciliary escalator. This is a necessary but not sufficient component of the pathogenesis of P. aeruginosa in CF that is well documented and supported by the work of Boucher and colleagues [13].…”

mentioning

confidence: 96%

“…Therefore, relying on observations made from the pathologic and histopathologic analysis of affected tissues provides substantial insight into the pathogenesis of this disease. Observations of the CF airway epithelium in tissues taken at autopsy or transplant [5][6][7] and observations made during experimental infection of WT and transgenic CF mice [8] clearly show that P. aeruginosa rarely binds to the airway epithelial cells in the CF lung but does so vigorously in mice expressing WT-CFTR (Figure 1a-d).The bacteria in the CF mouse are not observed interacting with the epithelium (Figure 1e,f) but rather found primarily within the mucus (Figure 1g,h), as in CF patients [7], where P. aeruginosa is primarily visualized to be trapped in mucus plugs that predominantly form in the airways [7]. In acutely-infected WT mice, P. aeruginosa cells trapped in the mucus are also readily seen (not shown), but these organisms are effectively cleared from the lung [8].…”

mentioning

confidence: 99%

“…Although many studies, conducted almost exclusively in υitro using cultured cells, have proposed that other P. aeruginosa surface factors such as pili, lectins and other adhesins can influence epithelial cells and initiate such responses as activation of the NF-κB innate immune response pathway associated with subsequent proinflammatory gene expression [40], this does not appear too relevant to CF as P. aeruginosa is never observed to bind to the CF epithelium in υiυo [5][6][7]. Furthermore, this organism only minimally binds to the respiratory epithelium of transgenic CF mice within hours of experimental infection [8]. Because it is not known what initially occurs in the CF lung after infection with P. aeruginosa, the available data best support a conclusion that whatever CFTR-independent interactions are occurring between P. aeruginosa and the CF airway epithelium, they do not contribute to host clearance and resistance to infection but might be important in the inappropriate inflammatory responses that do emerge within the CF lung and are significant components of pathology during chronic infection.…”

mentioning

confidence: 99%

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Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

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100

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Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism. Pseudomonas aeruginosa in cystic fibrosisCystic fibrosis (CF) is unique among human genetic disorders in that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein whose primary function described to date has been to regulate conductance of ions in and out of cells and intracellular vacuoles, lead to hypersusceptibility to chronic lung infection. Human diseases wherein individuals homozygous for mutant genes are predisposed to infections serve as a firm foundation for understanding the molecular, cellular, physiologic and immunologic aspects of normal and compromised resistance to infection. CF is not just a prime example of how we can learn about normal and pathologic states; it could, in fact, be the only known human genetically determined disease wherein infection with a single pathogen -Pseudomonas aeruginosa -drives the vast majority of morbidity, clinical deterioration and ultimately life-shortening mortality encountered in this disease. In humans with significant compromises to their immune system, such as advanced AIDS, we would normally expect to see a plethora of pathogens take advantage of this debilitated state, but this is not the case in CF.CF is characterized by the emergence and persistence of (and, ultimately, the inability to clear) chronic infection with a variant of P. aeruginosa (mucoid P. aeruginosa) that overproduces a surface polysaccharide known as alginate. The organism undergoes other significant genetic adaptations and selections within the CF lung, and it is the emergence of mucoid P. aeruginosa that is the primary determinant of the clinical course of this disease [1,2]. In those individuals with either an uncommon but fortuitous protective immune response to specific P. aeruginosa antigens [3,4] Histopathologic basis for defining relevant interactions between P.aeruginosa and the CF airway epitheliumAlthough CF is a multisystem disease characterized by GI and nutritional abnormalities, salt loss syndromes and male urogenital abnormalities, the major clinical problem for CF patients is chronic sinopulmonary disease. Therefore, relying on observations made fr...

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Ceramide in Pseudomonas aeruginosa infections

Riethmüller

Riehle

Grassmé

et al. 2007

Euro J Lipid Sci & Tech

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Ceramide in Pseudomonas aeruginosa infectionsCystic fibrosis (CF), the most common autosomal recessive disorder, at least in western countries, is caused by mutations of the cystic fibrosis transmembranous conductance regulator (CFTR) molecule and affects approximately 80,000 patients in Europe and the USA. Most, if not all, CF patients develop a chronic pulmonary infection with Pseudomonas aeruginosa. At present it is unknown why CF patients are highly sensitive to P. aeruginosa infections, and most importantly, no curative treatment for CF is available. P. aeruginosa infection results in an activation of the enzyme acid sphingomyelinase which catalyzes the release of ceramide from sphingomyelin in the cell membrane. Ceramide forms large ceramide-enriched membrane domains that are required for internalization of bacteria, induction of cell death in infected cells and a controlled release of cytokines from infected cells. Ceramide-enriched membrane platforms seem to serve the reorganization of receptors and intracellular signaling molecules involved in the infection of mammalian cells with P. aeruginosa. The significance of the acid sphingomyelinase and ceramide for the infection of mammalian cells with P. aeruginosa was demonstrated on mice genetically deficient for the acid sphingomyelinase. Further studies with N. gonorrhoeae, S. aureus and rhinoviruses indicate that ceramide-enriched membrane domains are also important for the infection of mammalian cells with other bacterial and viral pathogens, suggesting a general role of these membrane domains in infectious biology.

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Transgenic Cystic Fibrosis Mice Exhibit Reduced Early Clearance of Pseudomonas aeruginosa from the Respiratory Tract

Cited by 100 publications

References 33 publications

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Ceramide in Pseudomonas aeruginosa infections

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