scholarly journals D-BMAP18 Antimicrobial Peptide Is Active In vitro, Resists to Pulmonary Proteases but Loses Its Activity in a Murine Model of Pseudomonas aeruginosa Lung Infection

2017 ◽  
Vol 5 ◽  
Author(s):  
Mario Mardirossian ◽  
Arianna Pompilio ◽  
Margherita Degasperi ◽  
Giulia Runti ◽  
Sabrina Pacor ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Peptide ◽  
Murine Model ◽  
Lung Infection

scholarly journals Anti-Inflammatory Effects of RTD-1 in a Murine Model of Chronic Pseudomonas aeruginosa Lung Infection: Inhibition of NF-κB, Inflammasome Gene Expression, and Pro-IL-1β Biosynthesis

Antibiotics ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1043
Author(s):  
Mansour A. Dughbaj ◽  
Jordanna G. Jayne ◽  
A Young J. Park ◽  
Timothy J. Bensman ◽  
Marquerita Algorri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pseudomonas Aeruginosa ◽  
Microarray Analysis ◽  
Lung Tissue ◽  
Murine Model ◽  
Lung Infection ◽  
Cell Counts ◽  
Tissue Homogenates ◽  
Anti Inflammatory

Vicious cycles of chronic airway obstruction, lung infections with Pseudomonas aeruginosa, and neutrophil-dominated inflammation contribute to morbidity and mortality in cystic fibrosis (CF) patients. Rhesus theta defensin-1 (RTD-1) is an antimicrobial macrocyclic peptide with immunomodulatory properties. Our objective was to investigate the anti-inflammatory effect of RTD-1 in a murine model of chronic P. aeruginosa lung infection. Mice received nebulized RTD-1 daily for 6 days. Bacterial burden, leukocyte counts, and cytokine concentrations were evaluated. Microarray analysis was performed on bronchoalveolar lavage fluid (BALF) cells and lung tissue homogenates. In vitro effects of RTD-1 in THP-1 cells were assessed using quantitative reverse transcription PCR, enzyme-linked immunosorbent assays, immunoblots, confocal microscopy, enzymatic activity assays, and NF-κB-reporter assays. RTD-1 significantly reduced lung white blood cell counts on days 3 (−54.95%; p = 0.0003) and 7 (−31.71%; p = 0.0097). Microarray analysis of lung tissue homogenates and BALF cells revealed that RTD-1 significantly reduced proinflammatory gene expression, particularly inflammasome-related genes (nod-like receptor protein 3, Mediterranean fever gene, interleukin (IL)-1α, and IL-1β) relative to the control. In vitro studies demonstrated NF–κB activation was reduced two-fold (p ≤ 0.0001) by RTD-1 treatment. Immunoblots revealed that RTD-1 treatment inhibited proIL-1β biosynthesis. Additionally, RTD-1 treatment was associated with a reduction in caspase-1 activation (FC = −1.79; p = 0.0052). RTD-1 exhibited potent anti-inflammatory activity in chronically infected mice. Importantly, RTD-1 inhibits inflammasome activity, which is possibly a downstream effect of NF-κB modulation. These findings support that this immunomodulatory peptide may be a promising therapeutic for CF-associated lung disease.

Lactobacilli intra-tracheal administration protects from Pseudomonas aeruginosa pulmonary infection in mice – a proof of concept

2019 ◽  
Vol 10 (8) ◽  
pp. 893-900 ◽  
Author(s):  
M.S. Fangous ◽  
Y. Alexandre ◽  
N. Hymery ◽  
S. Gouriou ◽  
D. Arzur ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Murine Model ◽  
Alveolar Epithelial Cell ◽  
A549 Cells ◽  
Respiratory Pathogen ◽  
Public Health Issue ◽  
Epithelial Cell Line ◽  
High Morbidity ◽  
Respiratory Pathogens

The spreading of antibiotic resistance is a major public health issue, which requires alternative treatments to antibiotics. Lactobacilli have shown abilities to prevent pneumonia in clinical studies when given by oral route, certainly through the gut-lung axis involvement. Rationally, respiratory administration of lactobacilli has been developed and studied in murine model, to prevent from respiratory pathogens. It allows a direct effect of probiotics into the respiratory system. To our knowledge, no study has ever focused on the effect of probiotic intra-respiratory administration to prevent from Pseudomonas aeruginosa (PA) pneumonia, a major respiratory pathogen associated with high morbidity rates. In this study, we evaluated the beneficial activity of three Lactobacillus strains (Lactobacillus fermentum K.C6.3.1E, Lactobacillus zeae Od.76, Lactobacillus paracasei ES.D.88) previously screened by ourselves and known to be particularly efficient in vitro in inhibiting PAO1 virulence factors. Cytotoxic assays in alveolar epithelial cell line A549 were performed, followed by the comparison of two lactobacilli prophylactic protocols (one or two administrations) by intra-tracheal administration in a C57BL/6 murine model of PA pneumonia. A549 cells viability was improved from 23 to 75% when lactobacilli were administered before PAO1 incubation, demonstrating a protective effect (P<0.001). A significant decrease of 2 log of PAO1 was observed 4 h after PAO1 instillation (3×106 cfu/mouse) in both groups receiving lactobacilli (9×106 cfu/mouse) compared to PAO1 group (P<0.05). One single prophylactic administration of lactobacilli significantly decreased the secretion by 50% in bronchoalveolar lavages of interleukin (IL)-6 and tumour necrosis factor-α compared to PAO1. No difference of secretion was observed for the IL-10 secretion, whatever the prophylactic study design. This is the first study highlighting that direct lung administration of Lactobacillus strains protect against PA pneumonia. Next step will be to decipher the mechanisms involved before developing this novel approach for human applications.

scholarly journals Microbial Growth Inhibition by Alternating Electric Fields in Mice with Pseudomonas aeruginosa Lung Infection

2010 ◽  
Vol 54 (8) ◽  
pp. 3212-3218 ◽  
Author(s):  
Moshe Giladi ◽  
Yaara Porat ◽  
Alexandra Blatt ◽  
Esther Shmueli ◽  
Yoram Wasserman ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Growth Inhibition ◽  
Electric Fields ◽  
Bacterial Growth ◽  
Lung Infection ◽  
Alternating Electric Fields ◽  
Microbial Growth Inhibition ◽  
Bacterial Growth Inhibition

ABSTRACT High-frequency, low-intensity electric fields generated by insulated electrodes have previously been shown to inhibit bacterial growth in vitro. In the present study, we tested the effect of these antimicrobial fields (AMFields) on the development of lung infection caused by Pseudomonas aeruginosa in mice. We demonstrate that AMFields (10 MHz) significantly inhibit bacterial growth in vivo, both as a stand-alone treatment and in combination with ceftazidime. In addition, we show that peripheral (skin) heating of about 2°C can contribute to bacterial growth inhibition in the lungs of mice. We suggest that the combination of alternating electric fields, together with the heat produced during their application, may serve as a novel antibacterial treatment modality.

Co-administration of aqueous ginseng extract with tobramycin stimulates the pro-inflammatory response and promotes the killing of Pseudomonas aeruginosa in the lungs of infected rats

2013 ◽  
Vol 91 (11) ◽  
pp. 935-940 ◽  
Author(s):  
Misagh Alipour ◽  
Abdelwahab Omri ◽  
Edmund M.K. Lui ◽  
Zacharias E. Suntres
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Body Mass ◽  
Intratracheal Instillation ◽  
Lung Infection ◽  
Male Rats ◽  
Control Group ◽  
Ginseng Extract ◽  
Gm Csf

North American ginseng is known to have immunomodulatory and antipseudomonal properties in vitro. In this study we investigated the effects of aqueous ginseng extract, either alone or in a combination with the antibiotic tobramycin, in an animal model of chronic Pseudomonas aeruginosa lung infection. The lungs of male rats (n = 5) were infected with P. aeruginosa (2 × 108 cfu/mL) in agar-beads by intratracheal instillation. Starting on day 7 post-infection, animals were treated daily for 3 consecutive days with saline, tobramycin (300 μg/kg body mass, intratracheal), and (or) ginseng (100 mg/kg body mass, subcutaneous); animals were sacrificed 24 h after the third drug treatment. Lung bacteria counts, cytokine levels in sera, and lung histopathology were examined. The treatment of infected animals with tobramycin [6.6 × 104 colony forming units (cfu)], ginseng (5.3 × 104 cfu), or tobramycin plus ginseng (2.0 × 103 cfu) lessened the lung infection compared with the control group (saline treated) (6.0 × 106 cfu). The levels of pro-inflammatory cytokines (IL-2, IL-4, IL-6, IL-12p70, IFN-γ, GM-CSF, TNF-α) in infected animals were significantly increased with co-treatment of ginseng plus tobramycin. These data suggest that co-administration of aqueous ginseng extract and tobramycin stimulated the pro-inflammatory response and promoted the killing of P. aeruginosa.

scholarly journals De novo-derived cationic antimicrobial peptide activity in a murine model of Pseudomonas aeruginosa bacteraemia

2007 ◽  
Vol 60 (3) ◽  
pp. 669-672 ◽  
Author(s):  
Berthony Deslouches ◽  
Ivan A. Gonzalez ◽  
Dilhari DeAlmeida ◽  
Kazi Islam ◽  
Chad Steele ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Peptide ◽  
Murine Model ◽  
De Novo ◽  
Cationic Antimicrobial Peptide

scholarly journals Contribution of IL-38 in Lung Immunity During Pseudomonas Aeruginosa-Induced Pneumonia

2021 ◽  
Author(s):  
Qiang Wei ◽  
Xi Chen ◽  
Chuanjiang Wang
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Murine Model ◽  
Cell Apoptosis ◽  
Protective Role ◽  
Bacterial Removal ◽  
Cytokine Levels ◽  
New Type ◽  
Treg Differentiation

Abstract Objective: Interleukin-38 (IL-38), a new type of cytokine, is involved in processes such as tissue repair, inflammatory response, and immune response. However, its function in pneumonia caused by Pseudomonas aeruginosa is still unclear.Methods: In this study, we detected circulating IL-38 in adults affected by pneumonia caused by P. aeruginosa. The P. aeruginosa-induced pneumonia WT murine model was adopted to evaluate the effect of IL-38 on Treg differentiation, cell apoptosis, survival, tissue damage, inflammation, and bacterial removal.Results: IL-38 is insufficiently secreted in patients who died of P.A. pneumonia.Recombinant IL-38 improved survival, whereas anti-IL-38 antibody reduced survival in the experimental pneumonia murine model. IL-38 exposure reduced the inflammatory response, as suggested by the lung injury, and reduced cytokine levels (IL-1β, IL-6, IL-17A, TNF-α, and CXCL-1, but not IL-10). It also increased bacterial clearance and reduced cell apoptosis in the lungs. Furthermore, IL-38 was shown to reduce TBK1 expression in vitro when naïve CD4+ T lymphocytes were differentiated to Tregs and played a protective role in P.A. pneumonia.Conclusions: To summarize, the above findings provide additional insights into the mechanism of IL-38 in the treatment of P.A. pneumonia.

scholarly journals 1066. In Vitro and in Vivo Antimicrobial Activity of Cefiderocol and Comparators against Achromobacter spp

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S625-S626
Author(s):  
Ryuichiro Nakai ◽  
Ayaka makino ◽  
Hitomi Hama ◽  
Toriko Yoshitomi ◽  
Rio Nakamura ◽  
...  
Keyword(s):  
Rat Model ◽  
Murine Model ◽  
Lung Infection ◽  
Vitro Activity ◽  
Infection Model ◽  
In Vitro Activity ◽  
Independent Contractor ◽  
In Vivo Efficacy

Abstract Background Achromobacter spp. is intrinsically resistant to multiple antibiotics, and the treatment options are limited. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active against a wide variety of aerobic Gram-negative bacteria, including carbapenem-resistant strains. In this study, in vitro and in vivo antibacterial activity of CFDC against Achromobacter spp. was evaluated. Methods A total of 334 global isolates collected by IHMA from 39 countries in 2015-2019 were used. Minimum inhibitory concentrations (MICs) of CFDC and comparators were determined by broth microdilution method using iron-depleted CAMHB or CAMHB, respectively, as recommended by CLSI guidelines. In vivo efficacy of CFDC was compared with meropenem (MEM), piperacillin-tazobactam (PIP/TAZ), ceftazidime (CAZ), and ciprofloxacin (CIP) in a neutropenic murine lung infection model (n=5), and compared with MEM in a immunocompetent rat lung infection model (n=3-7) caused by 2 A. xylosoxydans. In the murine model, treatment was given 2, 5, and 8 hours post-infection, and the numbers of viable cfu in lungs were determined 24 hours post-infection. In the rat model, the humanized PK in plasma resulting from CFDC 2 g every 8 h (3-h infusion) or meropenem 1 g every 8 h (0.5-h infusion) were recreated via continuous intravenous infusion for 4 days, following which cfu in lungs were determined. Results CFDC showed in vitro activity with MIC50/90 of 0.06/0.5 µg/mL against 334 Achromobacter spp. Only 7 isolates (2.1%) had MICs &gt; 4 µg/mL. These were the lowest values among all compound tested (Table). In the murine model, CFDC caused &gt; 1.5 log10 decrease of viable cfu in lungs at 100 mg/kg dose (%fT &gt;MIC: &lt; 50%) from baseline control against both of strains (CFDC MIC: 0.5 and 2 µg/mL) (P&lt; 0.05). No decrease of cfu in lungs was observed for the comparators at 100 mg/kg (MEM, PIP/TAZ, CAZ, and CIP MICs were &gt;16, &gt;64, &gt;32, and &gt;8 µg/mL, respectively). In the rat model, humanized CFDC dosing reduced the viable cfu by &gt;1 log10 CFU/lung compared with baseline controls (P&lt; 0.05). MEM showed no significant activity. In vitro activity of CFDC and comparator agents against Achromobacter spp. 334 Achromobacter spp. isolates collected from 2015 and 2019. The majority of isolates tested were A. xylosoxidans (312/334; 93.4%), followed by A. insolitus (11/334; 3.3%), Achromobacter sp. (8/334; 2.4%), A. denitrificans (2/334; 0.6%), and A. piechaudii (1/334; 0.3%). Conclusion CFDC showed potent in vivo efficacy reflecting in vitro activity against A. xylosoxidans. The results suggested that CFDC has the potential to be an effective therapeutic option for Achromobacter spp. infections. Disclosures Ryuichiro Nakai, MSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Ayaka makino, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Yoshinori Yamano, PhD, Shionogi (Employee)

scholarly journals Adipose-Derived Mesenchymal Stem Cells Ameliorating Pseudomonas aeruginosa–induced Acute Lung Infection via Inhibition of NLRC4 Inflammasome

2021 ◽  
Vol 10 ◽  
Author(s):  
Lu-lu Li ◽  
Ying-gang Zhu ◽  
Xin-ming Jia ◽  
Dong Liu ◽  
Jie-ming Qu
Keyword(s):  
Stem Cells ◽  
Pseudomonas Aeruginosa ◽  
Mesenchymal Stem Cells ◽  
Lung Tissue ◽  
Pulmonary Infection ◽  
Bacterial Load ◽  
Lung Infection ◽  
Inflammasome Activation ◽  
Macrophage Phagocytosis

BackgroundPseudomonas aeruginosa (PA) is one of the most common Gram-negative bacteria causing hospital-acquired pulmonary infection, with high drug resistance and mortality. Therefore, it is urgent to introduce new non-antibiotic treatment strategies. Mesenchymal stem cells (MSCs), as important members of the stem cell family, were demonstrated to alleviate pathological damage in acute lung injury. However, the potential mechanism how MSC alleviate acute lung infection caused by PA remains unclear.ObjectiveThe purpose of this study was to investigate the effects of Adipose-derived mesenchymal stem cells (ASCs) on acute pulmonary infections and the possible mechanisms how ASCs reduce pulmonary inflammation induced by PA.MethodsThe therapeutic and mechanistic effects of ASCs on PA pulmonary infection were evaluated respectively in a murine model as well as in an in vitro model stimulated by PA and co-cultured with ASCs.Results1. ASCs treatment significantly reduced the bacterial load, inflammation of lung tissue and histopathological damage by PA. 2. PA infection mainly activated Nod-like receptor containing a caspase activating and recruitment domain 4 (NLRC4) inflammasome in the lung of mice. ASCs attenuated acute lung infection in mice by inhibiting NLRC4 inflammasome activation. 3. NLRC4−/− mice showed a significant improvement in survival rate and lung bacterial load after PA infection. 4. ASCs mainly increased expression and secretion of STC‐1 in response to PA‐stimulated NLRC4 inflammasome activation.ConclusionsPA infection attenuated macrophage phagocytosis through activation of NLRC4 inflammasome in macrophages, which eventually led to pulmonary inflammatory damage in mouse; ASCs reduced the activation of NLRC4 inflammasome in macrophages induced by PA infection, thereby increasing the phagocytic ability of macrophages, and ultimately improving lung tissue damage in mouse; ASCs may inhibit NLRC4 inflammasome through the secretion of STC-1.

scholarly journals Antibodies Against Pseudomonas aeruginosa Alkaline Protease Directly Enhance Disruption of Neutrophil Extracellular Traps Mediated by This Enzyme

2021 ◽  
Vol 12 ◽  
Author(s):  
Chendi Jing ◽  
Chenghua Liu ◽  
Yu Liu ◽  
Ruli Feng ◽  
Run Cao ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Alkaline Protease ◽  
Chronic Infection ◽  
Active Sites ◽  
Neutrophil Extracellular Traps ◽  
Lung Infection ◽  
Bacterial Burden ◽  
Extracellular Traps

Extracellular traps released by neutrophils (NETs) are essential for the clearance of Pseudomonas aeruginosa. Alkaline protease (AprA) secreted by P. aeruginosa negatively correlates with clinical improvement. Moreover, anti-AprA in patients with cystic fibrosis (CF) can help identify patients with aggressive forms of chronic infection. However, the mechanism underlying the clinical outcomes remains unclear. We demonstrated that aprA deficiency in P. aeruginosa decreased the bacterial burden and reduced lung infection. AprA degraded NET components in vitro and in vivo but did not affect NET formation. Importantly, antibodies induced by AprA acted as an agonist and directly enhanced the degrading activities of AprA. Moreover, antisera from patients with P. aeruginosa infection exhibited antibody-dependent enhancement (ADE) similar to that of the antibodies we prepared. Our further investigations showed that the interaction between AprA and the specific antibodies might make the enzyme active sites better exposed, and subsequently enhance the recognition of substrates and accelerate the degradation. Our findings revealed that AprA secreted by P. aeruginosa may aggravate infection by destroying formed NETs, an effect that was further enhanced by its antibodies.

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