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

Paternò, Salvatore; Pisani, Laura; Zanconato, Stefania; Ferraro, Valentina Agnese; Carraro, Silvia

doi:10.3390/ijms242216159

Cited by 5 publications

(1 citation statement)

References 53 publications

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“…In these cells, NO regulates ciliary beating frequency via cAMP and cGMP. Thus, cAMP and cGMP activate protein kinases A and G, which phosphorylate dynein light chains, increasing ciliary beating, which is deficient in PCD patients [19]. Our results agree with these previous reports and support the hypothesis that the low nNO levels observed in PCD patients are due to a decreased biosynthesis of the molecule since, at the cellular level, we have observed that these levels are significantly lower.…”

supporting

confidence: 92%

Redox Imbalance in Nasal Epithelial Cells of Primary Ciliary Dyskinesia Patients

Reula,

Castillo-Corullón,

Armengot

et al. 2024

Antioxidants

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Background: Primary Ciliary Dyskinesia (PCD) represents a rare condition marked by an abnormal mobility pattern of cilia and flagella, resulting in impaired mucociliary clearance. This deficiency leads to recurrent infections and persistent inflammation of the airways. While previous studies have indicated heightened oxidative stress levels in the exhaled breath condensate of pediatric PCD patients, the assessment of oxidative stress within the affected respiratory tissue remains unexplored. Aims: To assess the oxidative status of human nasal epithelial cells (NECs) in PCD patients. Methods: Thirty-five PCD patients and thirty-five healthy control subjects were prospectively included in the study. Levels of reactive oxygen species (ROS), reactive nitrogen species (RNS), glutathione (GSH), intracellular Ca2+, plasma membrane potential, and oxidative damage in lipids and proteins were measured. In addition, apoptosis and mitochondrial function were analyzed by flow cytometry in NECs. Results: NECs from PCD patients showed reduced levels of apoptosis (p = 0.004), superoxide anion (O2−, p = 0.018), peroxynitrite (ONOO−, p = 0.007), nitric oxide (NO, p = 0.007), mitochondrial hydrogen peroxide (mtH2O2, p < 0.0001), and mitochondrial superoxide anion (mtO2−, p = 0.0004) and increased mitochondrial mass (p = 0.009) compared to those from healthy individuals. No significant differences were observed in oxidized proteins (p = 0.137) and the oxidized/reduced lipid ratio (p = 0.7973). The oxidative profile of NEC cells in PCD patients, according to their ciliary motility, recurrent otitis, recurrent pneumonia, atelectasis, bronchiectasis, and situs inversus, showed no statistically significant differences in the parameters studied. Conversely, patients with chronic rhinosinusitis exhibited lower levels of ONOO− than PCD patients without this condition, with no significant differences related to other symptoms. Conclusions: Our findings strongly suggest the presence of a redox imbalance, specifically leaning toward a reductive state, in PCD patients.

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supporting

confidence: 92%

Redox Imbalance in Nasal Epithelial Cells of Primary Ciliary Dyskinesia Patients

Reula,

Castillo-Corullón,

Armengot

et al. 2024

Antioxidants

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Type 2 Biomarkers and Their Clinical Implications in Bronchiectasis: A Prospective Cohort Study

Chen,

Hou,

Chien

et al. 2024

Lung

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Purpose Bronchiectasis is predominantly marked by neutrophilic inflammation. The relevance of type 2 biomarkers in disease severity and exacerbation risk is poorly understood. This study explores the clinical significance of these biomarkers in bronchiectasis patients. Methods In a cross-sectional cohort study, bronchiectasis patients, excluding those with asthma or allergic bronchopulmonary aspergillosis, underwent clinical and radiological evaluations. Bronchoalveolar lavage samples were analyzed for cytokines and microbiology. Blood eosinophil count (BEC), serum total immunoglobulin E (IgE), and fractional exhaled nitric oxide (FeNO) were measured during stable disease states. Positive type 2 biomarkers were defined by established thresholds for BEC, total IgE, and FeNO. Results Among 130 patients, 15.3% demonstrated BEC ≥ 300 cells/μL, 26.1% showed elevated FeNO ≥ 25 ppb, and 36.9% had high serum total IgE ≥ 75 kU/L. Approximately 60% had at least one positive type 2 biomarker. The impact on clinical characteristics and disease severity was variable, highlighting BEC and FeNO as reflective of different facets of disease severity and exacerbation risk. The combination of low BEC with high FeNO appeared to indicate a lower risk of exacerbation. However, Pseudomonas aeruginosa colonization and a high neutrophil-to-lymphocyte ratio (NLR ≥ 3.0) were identified as more significant predictors of exacerbation frequency, independent of type 2 biomarker presence. Conclusions Our study underscores the distinct roles of type 2 biomarkers, highlighting BEC and FeNO, in bronchiectasis for assessing disease severity and predicting exacerbation risk. It advocates for a multi-biomarker strategy, incorporating these with microbiological and clinical assessments, for comprehensive patient management.

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Koolen-de Vries Syndrome causal geneKANSL1is required for motile ciliogenesis

Schmidt,

Terala,

McCluskey

et al. 2024

Preprint

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Koolen-de Vries Syndrome (KdVS), characterized by hypersociability, intellectual disability, and seizures, is caused by pathogenic variants in the geneKANSL1, which encodes a chromatin regulator in the NSL complex that also directly functions in mitotic spindle microtubule stability. Here we explored whether KANSL1 functions at the cilium, a microtubule-rich organelle critical for brain development, neuronal excitability, and sensory integration. Leveraging theXenopusmodel, we found that Kansl1 is highly expressed in developing ciliated tissues and localizes within motile cilia. Moreover,Kansl1depletion caused ciliogenesis defects that could be partially rescued by humanKANSL1. Based on these findings, we explored the prevalence of cilia-related clinical features including structural heart defects, hypogonadism, and structural respiratory defects among 99 individuals with KdVS, ages 1 month to 37 years old. To directly test if KdVS causes ciliary dysfunction in humans, we measured the well-established ciliary functional biomarker, nasal nitric oxide, in 11 affected individuals and observed a significant decrease when compared to unaffected family members. Together, this work establishes a ciliary contribution ofKANSL1mutations to KdVS. This work adds to a growing literature highlighting the relevance of the cilium to neurodevelopmental disorders, particularly to those impacting sociability. Going forward, KANSL1 provides a unique opportunity to study a monogenic mechanism of hypersociability that may be useful in elaborating the molecular underpinnings of social behavior.

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

Cited by 5 publications

References 53 publications

Redox Imbalance in Nasal Epithelial Cells of Primary Ciliary Dyskinesia Patients

Redox Imbalance in Nasal Epithelial Cells of Primary Ciliary Dyskinesia Patients

Type 2 Biomarkers and Their Clinical Implications in Bronchiectasis: A Prospective Cohort Study

Koolen-de Vries Syndrome causal geneKANSL1is required for motile ciliogenesis

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