scholarly journals Quantification of Phenotypic Variability of Lung Disease in Children with Cystic Fibrosis

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 803
Author(s):  
Mirjam Stahl ◽  
Eva Steinke ◽  
Marcus A. Mall
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Clinical Symptoms ◽  
Phenotypic Variability ◽  
Lung Structure ◽  
Multiple Breath Washout ◽  
Cftr Mutations ◽  
Magnetic Resonance Imaging Mri ◽  
And Function ◽  
The Impact

Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those carrying the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or CFTR mutations with comparable functional consequences. In most patients with CF, lung disease progresses from childhood to adulthood, but is already present in infants soon after birth. In addition to the CFTR genotype, the variability of early CF lung disease can be influenced by several factors, including modifier genes, age at diagnosis (following newborn screening vs. clinical symptoms) and environmental factors. The early onset of CF lung disease requires sensitive, noninvasive measures to detect and monitor changes in lung structure and function. In this context, we review recent progress with using multiple-breath washout (MBW) and lung magnetic resonance imaging (MRI) to detect and quantify CF lung disease from infancy to adulthood. Further, we discuss emerging data on the impact of variability of lung disease severity in the first years of life on long-term outcomes and the potential use of this information to improve personalized medicine for patients with CF.

Slow and fast lung compartments in cystic fibrosis measured by nitrogen multiple-breath washout

2014 ◽  
Vol 117 (7) ◽  
pp. 720-729 ◽  
Author(s):  
P. M. Gustafsson ◽  
P. D. Robinson ◽  
M. Gilljam ◽  
A. Lindblad ◽  
B. K. Houltz
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Disease Severity ◽  
Phase Iii ◽  
Healthy Controls ◽  
Lung Compartment ◽  
Wide Range ◽  
Multiple Breath Washout ◽  
Lung Disease Severity ◽  
And Function

Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis–derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28–18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis.

scholarly journals Irritable bowel syndrome: new insights into symptom mechanisms and advances in treatment

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 780 ◽  
Author(s):  
Robin Spiller
Keyword(s):  
Irritable Bowel Syndrome ◽  
New Agents ◽  
Enteric Nerves ◽  
Inflammatory Bowel ◽  
Magnetic Resonance Imaging Mri ◽  
Irritable Bowel ◽  
Fodmap Diet ◽  
And Function ◽  
The Impact

Despite being one of the most common conditions leading to gastroenterological referral, irritable bowel syndrome (IBS) is poorly understood. However, recent years have seen major advances. These include new understanding of the role of both inflammation and altered microbiota as well as the impact of dietary intolerances as illuminated by magnetic resonance imaging (MRI), which has thrown new light on IBS. This article will review new data on how excessive bile acid secretion mediates diarrhea and evidence from post infectious IBS which has shown how gut inflammation can alter gut microbiota and function. Studies of patients with inflammatory bowel disease (IBD) have also shown that even when inflammation is in remission, the altered enteric nerves and abnormal microbiota can generate IBS-like symptoms. The efficacy of the low FODMAP diet as a treatment for bloating, flatulence, and abdominal discomfort has been demonstrated by randomized controlled trials. MRI studies, which can quantify intestinal volumes, have provided new insights into how FODMAPs cause symptoms. This article will focus on these areas together with recent trials of new agents, which this author believes will alter clinical practice within the foreseeable future.

scholarly journals Damaged lung gas exchange function of discharged COVID-19 patients detected by hyperpolarized 129Xe MRI

2020 ◽  
Vol 7 (1) ◽  
pp. eabc8180
Author(s):  
Haidong Li ◽  
Xiuchao Zhao ◽  
Yujin Wang ◽  
Xin Lou ◽  
Shizhen Chen ◽  
...  
Keyword(s):  
Lung Function ◽  
Gas Exchange ◽  
Recovery Process ◽  
Blood Exchange ◽  
Structural Abnormalities ◽  
Hyperpolarized 129Xe ◽  
Magnetic Resonance Imaging Mri ◽  
And Function ◽  
Exchange Function ◽  
The Impact

The recovery process of COVID-19 patients is unclear. Some recovered patients complain of continued shortness of breath. Vasculopathy has been reported in COVID-19, stressing the importance of probing pulmonary microstructure and function at the alveolar-capillary interface. While computed tomography (CT) detects structural abnormalities, little is known about the impact of disease on lung function. 129Xe magnetic resonance imaging (MRI) is a technique uniquely capable of assessing ventilation, microstructure, and gas exchange. Using 129Xe MRI, we found that COVID-19 patients show a higher rate of ventilation defects (5.9% versus 3.7%), unchanged microstructure, and longer gas-blood exchange time (43.5 ms versus 32.5 ms) compared with healthy individuals. These findings suggest that regional ventilation and alveolar airspace dimensions are relatively normal around the time of discharge, while gas-blood exchange function is diminished. This study establishes the feasibility of localized lung function measurements in COVID-19 patients and their potential usefulness as a supplement to structural imaging.

The aging lung

1999 ◽  
Vol 9 (2) ◽  
pp. 103-115 ◽  
Author(s):  
Christopher AE Dyer ◽  
Robert A Stockley
Keyword(s):  
Lung Disease ◽  
Elderly People ◽  
Human Lung ◽  
Environmental Pollutants ◽  
Tobacco Consumption ◽  
Structure And Function ◽  
Lung Structure ◽  
Pulmonary Changes ◽  
And Function ◽  
Disease Exposure

Over a lifetime, the human lung is exposed to a multitude of factors capable of altering its structure and function. The frequency of acute, self-limiting lung disease, exposure to environmental pollutants and previous tobacco consumption in elderly people makes it difficult to identify pulmonary changes that can be attributed to ‘normal aging’ alone. It is likely that all these factors may have some influence on both lung structure and function.

scholarly journals Cystic fibrosis transmembrane conductance regulator dysfunction in VIP knockout mice

2014 ◽  
Vol 307 (2) ◽  
pp. C195-C207 ◽  
Author(s):  
Nicole G. Alcolado ◽  
Dustin J. Conrad ◽  
Diogo Poroca ◽  
Mansong Li ◽  
Walaa Alshafie ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Knockout Mice ◽  
Cellular Localization ◽  
Intraperitoneal Administration ◽  
Smooth Muscles ◽  
Primary Role ◽  
Innate Defense ◽  
And Function ◽  
The Impact

Vasoactive intestinal peptide (VIP), a neuropeptide, controls multiple functions in exocrine tissues, including inflammation, and relaxation of airway and vascular smooth muscles, and regulates CFTR-dependent secretion, which contributes to mucus hydration and local innate defense of the lung. We had previously reported that VIP stimulates the VPAC1 receptor, PKCϵ signaling cascade, and increases CFTR stability and function at the apical membrane of airway epithelial cells by reducing its internalization rate. Moreover, prolonged VIP stimulation corrects the molecular defects associated with F508del, the most common CFTR mutation responsible for the genetic disease cystic fibrosis. In the present study, we have examined the impact of the absence of VIP on CFTR maturation, cellular localization, and function in vivo using VIP knockout mice. We have conducted pathological assessments and detected signs of lung and intestinal disease. Immunodetection methods have shown that the absence of VIP results in CFTR intracellular retention despite normal expression and maturation levels. A subsequent loss of CFTR-dependent chloride current was measured in functional assays with Ussing chamber analysis of the small intestine ex vivo, creating a cystic fibrosis-like condition. Interestingly, intraperitoneal administration of VIP corrected tissue abnormalities, close to the wild-type phenotype, as well as associated defects in the vital CFTR protein. The results show in vivo a primary role for VIP chronic exposure in CFTR membrane stability and function and confirm in vitro data.

scholarly journals The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Emily M. Nakada ◽  
Rui Sun ◽  
Utako Fujii ◽  
James G. Martin
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein ◽  
Lung Structure ◽  
Selective Translation ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.

Determinants of lung disease progression measured by lung clearance index in children with cystic fibrosis

2021 ◽  
pp. 2003380
Author(s):  
Sanja Stanojevic ◽  
Stephanie D. Davis ◽  
Lucy Perrem ◽  
Michelle Shaw ◽  
George Retsch-Bogart ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Disease Progression ◽  
Forced Expiratory Volume ◽  
School Age ◽  
Lung Clearance ◽  
Time Period ◽  
Early School ◽  
Lung Clearance Index ◽  
Multiple Breath Washout

BackgroundThe lung clearance index (LCI) measured by the multiple breath washout (MBW) test is sensitive to early lung disease in children with cystic fibrosis (CF). While LCI worsens during the preschool years in CF, there is limited evidence to clarify whether this continues during the early school age years, and whether the trajectory of disease progression as measured by LCI is modifiable.MethodsA cohort of children (healthy (HC) and CF) previously studied for 12 months as preschoolers were followed during school age (5–10 years). LCI was measured every 3 months for a period of 24 months using the Exhalyzer® D MBW nitrogen washout device. Linear mixed effects regression was used to model changes in LCI over time.ResultsA total of 582 MBW measurements in 48 healthy subjects and 845 measurements in 64 CF subjects were available. The majority of children with CF had elevated LCI at the first preschool and first school age visits (57.8% (37/64)), whereas all but six had normal forced expiratory volume in 1 s (FEV1) values at the first school age visit. During school age years, the course of disease was stable (−0.02 units·year−1 (95% CI −0.14; 0.10). LCI measured during preschool years, as well as the rate of LCI change during this time period, were important determinants of LCI and FEV1, at school age.ConclusionPreschool LCI was a major determinant of school age LCI; these findings further support that the preschool years are critical for early intervention strategies.

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