Inhaled nitric oxide decreases the bacterial load in a rat model of Pseudomonas aeruginosa pneumonia

Miller, Christopher C.J.; Hergott, Christopher A.; Rohan, Marta; Arsenault-Mehta, Kyle; Döring, Gerd; Mehta, Sanjay

doi:10.1016/j.jcf.2013.01.008

Cited by 51 publications

(45 citation statements)

References 16 publications

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“…This initial in vivo study did not indicate an anti-inflammatory effect using gNO. In a previous study regarding bacterial pneumonia that was induced by P. aeruginosa, no influence of NO treatment was observed on the inflammation parameters, which was consistent with the present results (9). By contrast, the authors identified a marked reduction in the bacterial load of pseudomonades.…”

Section: Discussionsupporting

confidence: 93%

“…The present study hypothesized that i) bacteria were killed and ii) corneal inflammation was reduced following gNO treatment. It might be a similar situation in our keratitis model as in the pneumonia model described in the study by Miller et al (9) where inflammation was not reduced in contrast to the bacterial load. The bacterial load was not determined in the present study, as bacterial load can only be determined in the whole globes, but not separately within the cornea alone, due to the small structure of the murine cornea.…”

Section: Discussionsupporting

confidence: 74%

“…In this regard photodynamic inactivation has been in experimental and clinical use throughout the last decade (6)(7)(8). Research on cystic fibrosis established an antimicrobial effect of gaseous nitric oxide (gNO) in infections with P. aeruginosa using a rat model (9). Furthermore, a study in white rabbits demonstrated that a treatment using 200 ppm gNO significantly reduced the bacterial load in wounds of the dorsal skin surface (10).…”

Section: Introductionmentioning

confidence: 99%

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Gaseous nitric oxide for the local treatment of bacterial keratitis in mice

Deichelbohrer

Seitz

et al. 2016

Biomedical Reports

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Abstract. The successful treatment of severe bacterial keratitis continues to be a challenge in animals and humans. In the present study the aim was to assess gaseous therapy using gaseous nitric oxide (gNO) in a murine model of Pseudomonas aeruginosa keratitis. The cornea of anesthetized mice was mechanically scratched and covered with a bacterial suspension of P. aeruginosa. One day later, the infected eyes were exposed to 200 ppm NO for 30 min. Three to seven days later the mice were sacrificed and the bulbi were obtained and processed for light microscopy. The read out parameter was the maximal corneal thickness and the severity of the hypopyon. The therapy with NO did not result in either a reduction of inflammation concerning the maximal corneal thickness or the severity of the hypopyon. The bacterial load was not investigated due to technical limitations. Thus, exposure to gNO did not reduce the local inflammation in P. aeruginosa induced murine keratitis at the investigated time-points. This does not exclude effects of NO on the bacterial load, and in experimental and human keratitis. IntroductionBacterial keratitis is a major cause of blindness worldwide with a high incidence (1). This is due to low hygiene standards and water quality with a greater risk of infection in poor countries. In addition, the widespread use of contact lenses and associated complications in wealthier countries contributes to severe keratitis (2,3). Staphylococcus aureus and Pseudomonas aeruginosa are two predominant gram-positive and gram-negative bacterial strains responsible for causing this disease (1,4,5). The resistance of bacteria to antibiotics is reducing the efficacy of bacterial keratitis treatment. Therefore, research into the development of novel therapeutic approaches is essential. In this regard photodynamic inactivation has been in experimental and clinical use throughout the last decade (6-8). Research on cystic fibrosis established an antimicrobial effect of gaseous nitric oxide (gNO) in infections with P. aeruginosa using a rat model (9). Furthermore, a study in white rabbits demonstrated that a treatment using 200 ppm gNO significantly reduced the bacterial load in wounds of the dorsal skin surface (10). Thus, in view of the possibility of a surface treatment for keratitis, this therapeutic strategy demonstrated a feasible approach.The aim of the current study was to evaluate gNO application as a potential treatment of experimental keratitis in vivo for the first time. However, this series of experiments did not serve as proof of the anti-inflammatory effect of gNO. Materials and methodsAnimals and anaesthesia. Young (age, 9-10.5 weeks) female C57BL/6 mice [n=19; standard housing conditions (3-5 animals per cage) with 12-h light/dark cycle, minimum 70% humidity and chow/water were provided ad libitum; Janvier Labs, Saint-Berthevin Cedex, France] were used in the present study. All animal care and experimental procedures were approved by the local governmental animal care committee (permit no. 58/2013) and wer...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Gaseous nitric oxide for the local treatment of bacterial keratitis in mice

Deichelbohrer

Seitz

et al. 2016

Biomedical Reports

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“…The potential of intermittent exposure to high levels of NO gas has been assessed in animal trials using rats. NO was delivered at 160 ppm (~7 µM NO) for 30 min every 4 h to rats with P. aeruginosa airway infection, and the results showed that the NO treatment was able to reduce the infection by more than 2 log [98]. Exposure to NO gas at 500 ppm (~20 µM NO) for 60 s every 24-48 h of external wounds colonised by S. aureus led to faster wound healing by 30%, compared to controls [99].…”

Section: At Higher Levels No May Be Effective At Killing Biofilmsmentioning

confidence: 99%

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

Barraud¹,

Kelso²,

Rice

et al. 2014

CPD

221

196

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Studies of the biofilm life cycle can identify novel targets and strategies for improving biofilm control measures. Of particular interest are dispersal events, where a subpopulation of cells is released from the biofilm community to search out and colonize new surfaces. Recently, the simple gas and ubiquitous biological signaling molecule nitric oxide (NO) was identified as a key mediator of biofilm dispersal conserved across microbial species. Here, we review the role and mechanisms of NO mediating dispersal in bacterial biofilms, and its potential for novel therapeutics. In contrast to previous attempts using high dose NO aimed at killing pathogens, the use of low, non-toxic NO signals (picomolar to nanomolar range) to disperse biofilms represents an innovative and highly favourable approach to improve infectious disease treatments. Further, several NO-based technologies have been developed that offer a versatile range of solutions to control biofilms, including: (i) NO-generating compounds with short or long half-lives and safe or inert residues, (ii) novel compounds for the targeted delivery of NO to infectious biofilms during systemic treatments, and (iii) novel NO-releasing materials and surface coatings for the prevention and dispersal of biofilms. Overall the use of low levels of NO exploiting its signaling properties to induce dispersal represents an unprecedented and promising strategy for the control of biofilms in clinical and industrial contexts. AbstractStudies of the biofilm life cycle can identify novel targets and strategies for improving biofilm control measures. Of particular interest are dispersal events, where a subpopulation of cells is released from the biofilm community to search out and colonize new surfaces. Recently, the simple gas and ubiquitous biological signaling molecule nitric oxide (NO) was identified as a key mediator of biofilm dispersal conserved across microbial species. Here, we review the role and mechanisms of NO mediating dispersal in bacterial biofilms, and its potential for novel therapeutics. In contrast to previous attempts using high dose NO aimed at killing pathogens, the use of low, non-toxic NO signals (picomolar to nanomolar range) to disperse biofilms represents an innovative and highly favourable approach to improve infectious disease treatments. Further, several NO-based technologies have been developed that offer a versatile range of solutions to control biofilms, including: (i) NO-generating compounds with short or long half-lives and safe or inert residues, (ii) novel compounds for the targeted delivery of NO to infectious biofilms during systemic treatments, and (iii) novel NO-releasing materials and surface coatings for the prevention and dispersal of biofilms. Overall the use of low levels of NO exploiting its signaling properties to induce dispersal represents an unprecedented and promising strategy for the control of biofilms in clinical and industrial contexts. 3 Increased antimicrobial tolerance in biofilms is the basis for chronic infecti...

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“…Nitric oxide (NO), an endogenously produced free radical that can disperse (12,13) and eradicate (14,15) biofilms, holds particular promise as an alternative to current antibiotic treatments. Gaseous NO has been repeatedly used to eradicate P. aeruginosa infections in small-animal models with no apparent toxicity (16,17). Under aerobic environments, NO reacts with molecular oxygen, superoxide, and hydrogen peroxide to form highly reactive intermediates (peroxynitrite, nitrogen dioxide, and dinitrogen trioxide).…”

mentioning

confidence: 99%

Antibacterial Action of Nitric Oxide-Releasing Chitosan Oligosaccharides against Pseudomonas aeruginosa under Aerobic and Anaerobic Conditions

Reighard

2015

Antimicrob Agents Chemother

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Chitosan oligosaccharides were modified with N-diazeniumdiolates to yield biocompatible nitric oxide (NO) donor scaffolds. The minimum bactericidal concentrations and MICs of the NO donors against Pseudomonas aeruginosa were compared under aerobic and anaerobic conditions. Differential antibacterial activities were primarily the result of NO scavenging by oxygen under aerobic environments and not changes in bacterial physiology. Bacterial killing was also tested against nonmucoid and mucoid biofilms and compared to that of tobramycin. Smaller NO payloads were required to eradicate P. aeruginosa biofilms under anaerobic versus aerobic conditions. Under oxygen-free environments, the NO treatment was 10-fold more effective at killing biofilms than tobramycin. These results demonstrate the potential utility of NO-releasing chitosan oligosaccharides under both aerobic and anaerobic environments. Pseudomonas aeruginosa is an opportunistic human pathogen that frequently colonizes people with compromised immune systems, such as those with cystic fibrosis (CF) or severe burn wounds (1). The success of P. aeruginosa as a pathogen is related to its multitude of virulence factors, which increase adherence to the host cells, induce inflammation, and disrupt the host immune response (1). Furthermore, P. aeruginosa is intrinsically resistant to many antibiotics due to low membrane permeability and increased expression of ␤-lactamases and efflux pumps (2-4). In addition to this native resistance, P. aeruginosa readily adapts to antibiotic challenge by acquiring resistance genes (3, 5) and forming protective, cooperative communities known as biofilms (6, 7).While all antibiotic resistance mechanisms are not fully understood, at least three main factors reduce antibiotic efficacy against bacterial biofilms compared to planktonic cells. First, P. aeruginosa in biofilms secretes a protective layer of exopolysaccharides that prevent the diffusion of antibiotics (7). In the context of cystic fibrosis, biofilm-bound P. aeruginosa exists predominantly as the mucoid phenotype, characterized by a secreted alginate matrix that provides a physical barrier against the host immune response and antibiotics (8). This exopolysaccharide matrix also prevents the diffusion of oxygen into biofilms, causing P. aeruginosa to switch from aerobic to anaerobic respiration (9). The reduced metabolic activity of P. aeruginosa undergoing anaerobic respiration protects the bacterium against traditional antibiotics that are most effective against rapidly dividing cells, including aminoglycosides and ␤-lactams (10, 11). Finally, biofilms produce persister cells (i.e., dormant bacteria that are highly resistant to chemical disinfectants and exhibit multidrug tolerance) much more frequently than planktonic bacterial cultures (3, 7).The failure of conventional antibiotics to treat P. aeruginosa biofilms and infections necessitates the development of new antibacterial agents. Nitric oxide (NO), an endogenously produced free radical that can disperse (12, 13) and ...

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Inhaled nitric oxide decreases the bacterial load in a rat model of Pseudomonas aeruginosa pneumonia

Cited by 51 publications

References 16 publications

Gaseous nitric oxide for the local treatment of bacterial keratitis in mice

Gaseous nitric oxide for the local treatment of bacterial keratitis in mice

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

Antibacterial Action of Nitric Oxide-Releasing Chitosan Oligosaccharides against Pseudomonas aeruginosa under Aerobic and Anaerobic Conditions

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