Signaling via Platelet-Activating Factor Receptors Accounts for the Impairment of Neutrophil Migration in Polymicrobial Sepsis

Moreno, Susana Elisa; Alves‐Filho, José C.; Rios-Santos, Fabrício; Silva, João; Ferreira, Sérgio Henrique; Cunha, Fernando Q.; Teixeira, Mauro Martins

doi:10.4049/jimmunol.177.2.1264

Cited by 48 publications

(40 citation statements)

References 59 publications

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“…Moreno et al (45) showed that blockade of PAFR signaling was associated with an enhancement of neutrophil migration to the infectious site in a model of polymicrobial sepsis, which is in line with our findings. Because in their study PAFR blockade was associated with decreased bacterial outgrowth, the increased neutrophil migration to the peritoneal cavity during PAFR blockade was unlikely to be the consequence of a higher bacterial load.…”

Section: Discussionsupporting

confidence: 82%

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Zoelen

Florquin²,

Meijers

et al. 2008

The Journal of Immunology

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Pseudomonas aeruginosa is a major cause of nosocomial pneumonia, which is associated with high morbidity and mortality. Because of its ubiquitous nature and its ability to develop resistance to antibiotics, it is a problematic pathogen from a treatment perspective. Platelet-activating factor receptor (PAFR) is involved in phagocytosis of several pathogens. To determine the role of PAFR in the innate immune response to P. aeruginosa pneumonia, pafr gene-deficient (PAFR−/−) mice and normal wild-type (Wt) mice were intranasally inoculated with P. aeruginosa. PAFR deficiency impaired host defense as reflected by increased bacterial outgrowth and dissemination in mice with a targeted deletion of the PAFR gene. PAFR−/− neutrophils showed a diminished phagocytosing capacity of P. aeruginosa in vitro. Relative to Wt mice, PAFR−/− mice demonstrated increased lung inflammation and injury as reflected by histopathology, relative lung weights and total protein concentrations in bronchoalveolar lavage fluid, which was accompanied by higher levels of proinflammatory cytokines in lung homogenates and plasma. In addition, PAFR deficiency was associated with exaggerated local and systemic activation of coagulation as determined by fibrin staining of lung tissue and pulmonary and plasma concentrations of thrombin-antithrombin complexes and D-dimer. These data suggest that PAFR is an essential component of an effective host response to P. aeruginosa pneumonia, at least partly via its contribution to the phagocytic properties of professional granulocytes. Additionally, our results indicate that PAFR signaling is not essential for the induction of a local and systemic inflammatory and procoagulant response to Pseudomonas pneumonia.

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Section: Discussionsupporting

confidence: 82%

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Zoelen

Florquin²,

Meijers

et al. 2008

The Journal of Immunology

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“…In contrast to clinical shock trials where the drug is given in patients already with disease, most experimental studies only evaluated the effects of preventive administration of PAFR antagonists. PAFR antagonists clearly lose their efficacy when administered after the inciting stimulus in models of septic or anaphylactic shock (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…4248 (5 mg/kg/dose, s.c., B.I.D) (23). In some experiments, mice were pretreated with non-immune serum or serum (1 single dose of 100 L of 1:10 dilution of stock serum in PBS, i.p., 60 min before inoculation) obtained from Rhesus monkeys previously infected with a known DEN-2 strain (31) (kindly donated by Dr Ricardo Galler, Fiocruz, Brazil).…”

mentioning

confidence: 99%

Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection

Souza

Fagundes

Sousa

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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112

107

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Severe dengue infection in humans causes a disease characterized by thrombocytopenia, increased levels of cytokines, increased vascular permeability, hemorrhage, and shock. Treatment is supportive. Activation of platelet-activating factor (PAF) receptor (PAFR) on endothelial cells and leukocytes induces increase in vascular permeability, hypotension, and production of cytokines. We hypothesized that activation of PAFR could account for the major systemic manifestations of dengue infection. Inoculation of adult mice with an adapted strain of Dengue virus caused a systemic disease, with several features of the infection in humans. In PAFR ؊/؊ mice, there was decreased thrombocytopenia, hemoconcentration, decreased systemic levels of cytokines, and delay of lethality, when compared with WT infected mice. Treatment with UK-74,505, an orally active PAFR antagonist, prevented the above-mentioned manifestations, as well as hypotension and increased vascular permeability, and decreased lethality, even when started 5 days after virus inoculation. Similar results were obtained with a distinct PAFR antagonist, PCA-4246. Despite decreased disease manifestation, viral loads were similar (PAFR ؊/؊ ) or lower (PAFR antagonist) than in WT mice. Thus, activation of PAFR plays a major role in the pathogenesis of experimental dengue infection, and its blockade prevents more severe disease manifestation after infection with no increase in systemic viral titers, suggesting that there is no interference in the ability of the murine host to deal with the infection. PAFR antagonists are diseasemodifying agents in experimental dengue infection.inflammation ͉ cytokines ͉ shock

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“…In vivo sepsis analysis was performed according to the method proposed by Moreno et al 33 involving intraperitoneal sepsis induction in mice using an injection containing a bacteria pool. For in vivo experiments, C57BL/6 mice were obtained from the Universidade Católica Dom Bosco, housed in temperature-controlled cages (22°C-24°C), and received food and water ad libitum.…”

Section: In Vivo Antibacterial Activitiesmentioning

confidence: 99%

Clavanin bacterial sepsis control using a novel methacrylate nanocarrier

Saúde¹,

Ombredane²,

Silva³

et al. 2014

IJN

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Controlling human pathogenic bacteria is a worldwide problem due to increasing bacterial resistance. This has prompted a number of studies investigating peptides isolated from marine animals as a possible alternative for control of human pathogen infections. Clavanins are antimicrobial peptides isolated from the marine tunicate Styela clava , showing 23 amino acid residues in length, cationic properties, and also high bactericidal activity. In spite of clear benefits from the use of peptides, currently 95% of peptide properties have limited pharmaceutical applicability, such as low solubility and short half-life in the circulatory system. Here, nanobiotechnology was used to encapsulate clavanin A in order to develop nanoantibiotics against bacterial sepsis. Clavanin was nanostructured using EUDRAGIT ® L 100-55 and RS 30 D solution (3:1 w:w). Atomic force, scanning electron microscopy and dynamic light scattering showed nanoparticles ranging from 120 to 372 nm in diameter, with a zeta potential of -7.16 mV and a polydispersity index of 0.123. Encapsulation rate of 98% was assessed by reversed-phase chromatography. In vitro bioassays showed that the nanostructured clavanin was partially able to control development of Staphylococcus aureus , Klebsiella pneumoniae , and Pseudomonas aeruginosa . Furthermore, nanostructures did not show hemolytic activity. In vivo sepsis bioassays were performed using C57BL6 mice strain inoculated with a polymicrobial suspension. Assays led to 100% survival rate under sub-lethal sepsis assays and 40% under lethal sepsis assays in the presence of nanoformulated clavanin A until the seventh day of the experiment. Data here reported indicated that nanostructured clavanin A form shows improved antimicrobial activity and has the potential to be used to treat polymicrobial infections.

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Signaling via Platelet-Activating Factor Receptors Accounts for the Impairment of Neutrophil Migration in Polymicrobial Sepsis

Cited by 48 publications

References 59 publications

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection

Clavanin bacterial sepsis control using a novel methacrylate nanocarrier

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