Total Sputum Nitrate plus Nitrite Is Raised during Acute  Pulmonary Infection in Cystic Fibrosis

Linnane, S.J.; Keatings, Vera M.; Costello, Christine; Moynihan, John B; O'connor, Clare M.; FitzGerald, M. X.; McLoughlin, Paul

doi:10.1164/ajrccm.158.1.9707096

Cited by 93 publications

(76 citation statements)

References 33 publications

(39 reference statements)

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“…Nitric oxide is a neutrophil derived inflammatory mediator, and nitrite is presumed to result from degradation within CF mucus. Although inducible nitric oxide synthase is poorly active in CF respiratory epithelium [13], excess neutrophil presence in CF airways could account for raised nitrite values [14]. Nitrite therefore represents a potentially useful inflammatory marker in CF, that requires further investigation in longitudinal studies.…”

Section: Discussionmentioning

confidence: 99%

Measurement of inflammatory markers in the breath condensate of children with cystic fibrosis

Cunningham

McColm

et al. 2000

Eur Respir J

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Identifying noninvasive markers of pulmonary inflammation would be useful in assessing new therapies in children. Breath condensate is a simple and potentially acceptable sample medium even in small children. The technique has previously been used in adults, but not children with cystic fibrosis.The technique was assessed in 36 children with cystic fibrosis (mean age 10.4 yrs) and 17 control subjects, analysing samples for nitrite, interleukin(IL)-8 and salivary and nasal contamination. Correlations were made between levels of the inflammatory markers and forced expiratory volume in one second/forced vital capacity, chest radiograph score and use of inhaled steroids.On samples without significant contamination (<10 u . L -1 amylase) nitrite was detected in 93% of samples at a median concentration of 3.0 mM compared with 50% of control samples at a median of 0.5 mM. Condensate amylase levels did not correlate with the nitrite value obtained (r=0.31). IL-8 was detected in 33% of CF samples.Breath condensate is an acceptable method of sample collection in children. Nitrite was raised in breath condensate from patients with cystic fibrosis when compared with control subjects. Eur Respir J 2000; 15: 955±957. Pulmonary inflammation in children with cystic fibrosis (CF) begins soon after birth [1], and arresting this progressive inflammation is central to CF research. It would be desirable therefore to identify a measure of pulmonary inflammation (single or combined), that is more sensitive than pulmonary function testing, noninvasive, repeatable and applicable to young children. The assessment of exhaled breath in CF has not been fruitful: nitric oxide levels are normal [2], or reduced [3] in CF when compared with control subjects, and exhaled pentane is raised in CF, but prone to gastrointestinal contamination [4].The measurement of inflammatory mediators in breath condensate (exhaled aerosolized bronchoalveolar lining fluid), might provide a noninvasive, direct assessment of pulmonary inflammation. Condensate is capable of carrying molecules <65 kDa [5]: that could include the majority of pro-inflammatory pulmonary cytokines that are increased in CF. Nitrite This technique, however, has not been applied to children with CF, and the aim of the current study was therefore to evaluate the reliability and acceptability of this technique, assessing whether children with CF have raised nitrite (like their adult counterparts [6]), and to assess for the first time whether IL-8, a dominant pro-inflammatory cytokine in CF [8], is found in measurable quantities in exhaled condensate. MethodsThe study was performed at the authors' regional paediatric CF centre (Edinburgh, Scotland, UK). Control samples were collected from children who were either staff relatives or attending fracture clinic with single stable fractures and no history of chronic respiratory illness. Children with CF were clinically stable at the time of assessment.The equipment for condensate collection has previously been used successfully in adults, ...

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Section: Discussionmentioning

confidence: 99%

Measurement of inflammatory markers in the breath condensate of children with cystic fibrosis

Cunningham

McColm

et al. 2000

Eur Respir J

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“…4). This lack of effect maybe be because nitrate was not added to the blood agar colony biofilms or the planktonic cultures and Dnr may play a role in controlling plcH transcription under other conditions where sources of nitric oxide are available, such as in the CF lung (259 mmol l 21 ) (Grasemann et al, 1998;Linnane et al, 1998). It is important to note that plcH mRNAs are detected across numerous samples, indicating that the regulation of this gene in vivo may be complex .…”

Section: Discussionmentioning

confidence: 99%

Global regulator Anr represses PlcH phospholipase activity in Pseudomonas aeruginosa when oxygen is limiting

et al. 2014

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Haemolytic phospholipase C (PlcH) is a potent virulence and colonization factor that is expressed at high levels by Pseudomonas aeruginosa within the mammalian host. The phosphorylcholine liberated from phosphatidylcholine and sphingomyelin by PlcH is further catabolized into molecules that both support growth and further induce plcH expression. We have shown previously that the catabolism of PlcH-released choline leads to increased activity of Anr, a global transcriptional regulator that promotes biofilm formation and virulence. Here, we demonstrated the presence of a negative feedback loop in which Anr repressed plcH transcription and we proposed that this regulation allowed for PlcH levels to be maintained in a way that promotes productive host-pathogen interactions. Evidence for Anr-mediated regulation of PlcH came from data showing that growth at low oxygen (1 %) repressed PlcH abundance and plcH transcription in the WT, and that plcH transcription was enhanced in an Danr mutant. The plcH promoter featured an Anr consensus sequence that was conserved across all P. aeruginosa genomes and mutation of conserved nucleotides within the Anr consensus sequence increased plcH expression under hypoxic conditions. The Anr-regulated transcription factor Dnr was not required for this effect. The loss of Anr was not sufficient to completely derepress plcH transcription as GbdR, a positive regulator of plcH, was required for expression. Overexpression of Anr was sufficient to repress plcH transcription even at 21 % oxygen. Anr repressed plcH expression and phospholipase C activity in a cell culture model for P. aeruginosa-epithelial cell interactions. INTRODUCTIONPseudomonas aeruginosa squanders few opportunities to colonize a vulnerable human host. In addition to engendering a range of nosocomial infections, including keratitis (Green et al., 2008), burn wounds (de Macedo & Santos, 2005), endocarditis (Baddour et al., 2005) and implanted medical devices (Hidron et al., 2008), it also colonizes the lungs of 80 % of persons with the heritable disease cystic fibrosis (CF) (Rajan & Saiman, 2002;Rosenfeld et al., 2003). Colonization by P. aeruginosa contributes to the decline of lung function in this patient population (Rajan & Saiman, 2002), due in part to its wide array of virulence factors that promote its growth and persistence within the host. One such virulence factor is the well-characterized exotoxin haemolytic phospholipase C (PlcH), which is secreted by P. aeruginosa when in association with eukaryotic hosts. PlcH is essential for virulence in co-culture with fungal filaments, on Arabidopsis leaves, in Galleria mellonella larvae and in mammalian hosts (Hogan & Kolter, 2002;Jander et al., 2000;Rahme et al., 2000), highlighting its importance in diverse models of infection.PlcH degrades the abundant phospholipids phosphatidylcholine (PC) and sphingomyelin, which are found in eukaryotic membranes and in lung surfactant (Berka & Vasil, 1982;Vasil, 2006). PC degradation releases both fatty acids and choline-containing c...

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“…Being an obligate respirer, P. aeruginosa is also capable of generating energy even in the absence of oxygen using As shown in Figure 2B, pH gradient across the inner membrane can still be generated when NO 3 - (43,44). This result suggests that P.…”

Section: Anaerobic Growth Of P Aeruginosamentioning

confidence: 92%

Anaerobiosis ofPseudomonas aeruginosa: Implications for Treatments of Airway Infection

Yoon

2010

J Bacteriol Virol

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Pseudomonas aeruginosa, as an opportunistic pathogen, establishes a chronic infection in the respiratory track of patients suffering from pneumonia and bronchiectasis, including cystic fibrosis. Biofilm formation inside the oversecreted mucus layer lining the patient airway and production of virulence factors, a process controlled by quorum sensing, are considered to be the major virulence determinants in P. aeruginosa pathogenesis. Recently, an abnormally thickened mucus layer was proven to be anaerobic. Given the fact that currently used antibiotics are less effective under anaerobic environments, these new findings lead us to change the way we confront P. aeruginosa infection. This article reviews pathological features of patient airways that become susceptible to P. aeruginosa infection and bacterial adaptation that contributes to the prolonged survival inside the patient airway.

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Total Sputum Nitrate plus Nitrite Is Raised during Acute Pulmonary Infection in Cystic Fibrosis

Cited by 93 publications

References 33 publications

Measurement of inflammatory markers in the breath condensate of children with cystic fibrosis

Measurement of inflammatory markers in the breath condensate of children with cystic fibrosis

Global regulator Anr represses PlcH phospholipase activity in Pseudomonas aeruginosa when oxygen is limiting

Anaerobiosis ofPseudomonas aeruginosa: Implications for Treatments of Airway Infection

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