Longitudinal Nitric Oxide Levels and Infections by Ultrastructure and Genotype in Primary Ciliary Dyskinesia

Pifferi, Massimo; Boner, Attilio; Gracci, Serena; Fonnesu, Rossella; Maj, Debora; Donzelli, Gabriele; Michelucci, Angela; Cangiotti, Angela Maria; Bertini, Veronica; Valetto, Angelo; Caligo, Maria A.; Miccoli, Mario; Peroni, Diego; Bush, Andrew

doi:10.1016/j.chest.2022.06.019

Cited by 4 publications

(2 citation statements)

References 36 publications

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“…Similarly, Pifferi et al [ 19 ] speculated that reduced nasal NO levels, as well as being a marker for PCD, may contribute to its pathophysiology. Very recently, in a large PCD cohort, lower nNO observed in patients with more severe genetic and/or ultrastructural PCD types was shown to correlate with greater lung function decline over time and higher nNO with a reduced likelihood of bacterial infection [ 48 ]. Taken together, NO production and motile ciliary defects seem to be interrelated in a complex way, forming a vicious circle.…”

Section: Discussionmentioning

confidence: 99%

Impaired Nitric Oxide Synthetase Activity in Primary Ciliary Dyskinesia—Data-Driven Hypothesis

Eggenkemper,

Schlegtendal,

Maier

et al. 2023

JCM

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Low nasal nitric oxide (nNO) is a typical feature of Primary Ciliary Dyskinesia (PCD). nNO is part of the PCD diagnostic algorithm due to its discriminative power against other lung diseases, such as cystic fibrosis (CF). However, the underlying pathomechanisms are elusive. To better understand NO dysregulation in PCD, the L-arginine/NO (Arg/NO) pathway in patients with PCD (pwPCD) and CF (pwCF) and in healthy control (HC) subjects was investigated. In a prospective, controlled study, we measured in 24 pwPCD, 25 age-matched pwCF, and 14 HC the concentrations of the NO precursors Arg and homoarginine (hArg), the arginase metabolite ornithine (Orn), the NO inhibitor asymmetric dimethylarginine (ADMA), and the major NO metabolites (nitrate, nitrite) in sputum, plasma, and urine using validated methods. In comparison to HC, the sputum contents (in µmol/mg) of L-Arg (PCD 18.43 vs. CF 329.46 vs. HC 9.86, p < 0.001) and of ADMA (PCD 0.055 vs. CF 0.015 vs. HC 0.010, p < 0.001) were higher. In contrast, the sputum contents (in µmol/mg) of nitrate and nitrite were lower in PCD compared to HC (nitrite 4.54 vs. 9.26, p = 0.023; nitrate 12.86 vs. 40.33, p = 0.008), but higher in CF (nitrite 16.28, p < 0.001; nitrate 56.83, p = 0.002). The metabolite concentrations in urine and plasma were similar in all groups. The results of our study indicate that PCD, unlike CF, is associated with impaired NO synthesis in the lung, presumably due to mechano-chemical uncoupling.

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Section: Discussionmentioning

confidence: 99%

Impaired Nitric Oxide Synthetase Activity in Primary Ciliary Dyskinesia—Data-Driven Hypothesis

Eggenkemper,

Schlegtendal,

Maier

et al. 2023

JCM

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“…Also, a recent study by Pifferi et al [28] evaluated longitudinally nNO levels in PCD patients. In this prospective study, patients with PCD were divided in two groups: (1) patients with specific gene mutations (i.e., biallelic mutations in CCDC39 and CCDC40) and ultrastructural abnormalities (i.e., inner dynein arm (IDA) and microtubular disorganization (MTD)) usually associated with worse pulmonary outcome over time (measured through the deterioration of spirometry and lung volumes); and (2) patients without those genetic and ultrastructural alterations and therefore likely to have a better lung function prognosis [29,30].…”

Section: Relationship Between Nno Genotypes and Ciliary Function: A M...mentioning

confidence: 99%

Role of Nasal Nitric Oxide in Primary Ciliary Dyskinesia and Other Respiratory Conditions in Children

Paternò,

Pisani,

Zanconato

et al. 2023

IJMS

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Nitric oxide (NO) is produced within the airways and released with exhalation. Nasal NO (nNO) can be measured in a non-invasive way, with different devices and techniques according to the age and cooperation of the patients. Here, we conducted a narrative review of the literature to examine the relationship between nNO and some respiratory diseases with a particular focus on primary ciliary dyskinesia (PCD). A total of 115 papers were assessed, and 50 were eventually included in the review. nNO in PCD is low (below 77 nL/min), and its measurement has a clear diagnostic value when evaluated in a clinically suggestive phenotype. Many studies have evaluated the role of NO as a molecular mediator as well as the association between nNO values and genotype or ciliary function. As far as other respiratory diseases are concerned, nNO is low in chronic rhinosinusitis and cystic fibrosis, while increased values have been found in allergic rhinitis. Nonetheless, the role in the diagnosis and prognosis of these conditions has not been fully clarified.

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Impact of TAS2R38 polymorphisms on nasal nitric oxide and Pseudomonas infections in primary ciliary dyskinesia: relation to genotype

Pifferi,

Boner,

Maj

et al. 2024

Thorax

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ObjectivePrimary ciliary dyskinesia (PCD) severity has been related to genotype and levels of nasal nitric oxide (nNO). The most common TAS2R38 haplotypes (PAV/PAV, PAV/AVI, AVI/AVI) encoding the bitter taste receptor can affect nNO levels and thus could play a role in the susceptibility to respiratory infections. We assessed the impact of these polymorphisms on nNO production andPseudomonas aeruginosa(P.a.) infections in different PCD genotypes.MethodsProspective, longitudinal, single-centre study in patients with PCD with known genotype and one of three TAS2R38 haplotypes evaluated for up to 10 years. We related nNO values to TAS2R38 haplotypes in all patients, and in the three most frequent genotypes (CCDC39/CCDC40,DNAH5,DNAH11). In the genetic group(s) with different mean trends of nNO in relation to the polymorphism, we evaluated longitudinal lung function as a clinical outcome measure. We also studied any associations between the prevalence of chronicP.a. infection and PAV alleles. Linear mixed-effects models were used to evaluate longitudinal associations.Results119 patients with PCD underwent 1116 study visits. Only in theDNAH11mutations group was there a mean trend of nNO production which was significantly higher in PAV/PAV than AVI/AVI haplotype (p=0.033), with a better trend in spirometric and plethysmographic parameters. In patients withDNAH11mutations the PAV allele was also associated with a significantly reduced prevalence of chronicP.a. infection.ConclusionTAS2R38 may be a modifier gene for PCD severity, but only in mild phenotype disease. Further study of TAS2R38 polymorphisms might enable new management strategies to prevent chronicP.a. infections.

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Longitudinal Nitric Oxide Levels and Infections by Ultrastructure and Genotype in Primary Ciliary Dyskinesia

Cited by 4 publications

References 36 publications

Impaired Nitric Oxide Synthetase Activity in Primary Ciliary Dyskinesia—Data-Driven Hypothesis

Impaired Nitric Oxide Synthetase Activity in Primary Ciliary Dyskinesia—Data-Driven Hypothesis

Role of Nasal Nitric Oxide in Primary Ciliary Dyskinesia and Other Respiratory Conditions in Children

Impact of TAS2R38 polymorphisms on nasal nitric oxide and Pseudomonas infections in primary ciliary dyskinesia: relation to genotype

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