Background Bronchial airway expression profiling has identified inflammatory subphenotypes of asthma, but the invasiveness of this technique has limited its application to childhood asthma. ...Objectives We sought to determine whether the nasal transcriptome can proxy expression changes in the lung airway transcriptome in asthmatic patients. We also sought to determine whether the nasal transcriptome can distinguish subphenotypes of asthma. Methods Whole-transcriptome RNA sequencing was performed on nasal airway brushings from 10 control subjects and 10 asthmatic subjects, which were compared with established bronchial and small-airway transcriptomes. Targeted RNA sequencing nasal expression analysis was used to profile 105 genes in 50 asthmatic subjects and 50 control subjects for differential expression and clustering analyses. Results We found 90.2% overlap in expressed genes and strong correlation in gene expression (ρ = .87) between the nasal and bronchial transcriptomes. Previously observed asthmatic bronchial differential expression was strongly correlated with asthmatic nasal differential expression (ρ = 0.77, P = 5.6 × 10−9 ). Clustering analysis identified TH 2-high and TH 2-low subjects differentiated by expression of 70 genes, including IL13 , IL5 , periostin (POSTN) , calcium-activated chloride channel regulator 1 (CLCA1) , and serpin peptidase inhibitor, clade B (SERPINB2) . TH 2-high subjects were more likely to have atopy (odds ratio, 10.3; P = 3.5 × 10−6 ), atopic asthma (odds ratio, 32.6; P = 6.9 × 10−7 ), high blood eosinophil counts (odds ratio, 9.1; P = 2.6 × 10−6 ), and rhinitis (odds ratio, 8.3; P = 4.1 × 10−6 ) compared with TH 2-low subjects. Nasal IL13 expression levels were 3.9-fold higher in asthmatic participants who experienced an asthma exacerbation in the past year ( P = .01). Several differentially expressed nasal genes were specific to asthma and independent of atopic status. Conclusion Nasal airway gene expression profiles largely recapitulate expression profiles in the lung airways. Nasal expression profiling can be used to identify subjects with IL13 -driven asthma and a TH 2-skewed systemic immune response.
The current usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis CT scan classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive ...effect of probable UIP on CT scan on histology and the effect of the promoter polymorphism in MUC5B (rs35705950) on histologic and CT scan UIP diagnosis. METHODS The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within 1 year of chest CT scan. UIP diagnosis on CT scan was categorized as inconsistent with, indeterminate, probable, or definite UIP by two to three pulmonary radiologists. Tissue slides were scored by two expert pulmonary pathologists. All subjects with available DNA (N = 200) were genotyped for rs35705950. RESULTS The proportion of CT scan diagnoses were as follows: inconsistent with (69 of 201, 34.3%), indeterminate (72 of 201, 35.8%), probable (34 of 201, 16.9%), and definite (26 of 201, 12.9%) UIP. Subjects with probable UIP on CT scan were more likely to have histologic probable/definite UIP than subjects with indeterminate UIP on CT scan (82.4% 28 of 34 vs 54.2% 39 of 72; P = .01). CT scan and microscopic honeycombing were not associated with each other ( P = .76). The minor (T) allele of the MUC5B polymorphism was associated with concordant CT scan and histologic UIP diagnosis ( P = .03). CONCLUSIONS Probable UIP on CT scan is associated with a higher rate of histologic UIP than indeterminate UIP on CT scan suggesting that they are distinct groups and should not be combined into a single CT scan category as currently recommended by guidelines. CT scan and microscopic honeycombing may be dissimilar entities. The T allele at rs35705950 predicts a UIP diagnosis by both chest CT scan and histology.
Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants ...in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF.
Variants in the gene encoding mucin 5B (
MUC5B
) have been associated with interstitial fibrosis. This study shows a relationship between the presence of the associated variants in
MUC5B
and ...interstitial lung abnormalities in participants in a Framingham study cohort.
Subclinical interstitial lung abnormalities are relatively common findings on imaging studies in smokers and elderly persons.
1
Accumulating evidence suggests that these abnormalities may precede the development of clinically relevant pulmonary fibrosis.
1
–
7
However, it is not known whether there is a genetic association between interstitial lung abnormalities and pulmonary fibrosis in the general population.
Recently, a single-nucleotide polymorphism (SNP) (rs35705950) in the promoter of the gene encoding mucin 5B (
MUC5B
) was shown to be associated with both familial interstitial pneumonia and sporadic idiopathic pulmonary fibrosis.
8
In addition, the
MUC5B
variant was associated with increased expression of MUC5B in . . .
Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disease with a median survival of only 3-5 years that is diagnosed using a combination of clinical, radiographic and pathologic criteria. ...Histologically, IPF is characterised by usual interstitial pneumonia (UIP), a fibrosing interstitial pneumonia with a pattern of heterogeneous, subpleural regions of fibrotic and remodelled lung. We hypothesised that gene expression profiles of lung tissue may identify molecular subtypes of disease that could classify subtypes of IPF/UIP that have clinical implications.
We collected transcriptional profiles on lung tissue from 119 patients with IPF/UIP and 50 non-diseased controls. Differential expression of individual transcripts was identified using an analysis of covariance (ANCOVA) model incorporating the clinical diagnosis of each patient as well as age, gender and smoking status. Validation was performed in an independent cohort of 111 IPF/UIP and 39 non-diseased controls. Our analysis identified two subtypes of IPF/UIP based on a strong molecular signature associated with expression of genes previously associated with fibrosis (matrix metalloproteinases, osteopontin, keratins), cilium genes and genes with unknown function. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing and higher expression of both the airway mucin gene MUC5B and the metalloproteinase MMP7, a gene recently implicated in attenuating ciliated cell differentiation during wound repair.
Expression of cilium genes appears to identify two unique molecular phenotypes of IPF/UIP. The different molecular profiles may be relevant to therapeutic responsiveness in patients with IPF/UIP.
Evolution of the Gain-of-Function MUC5B Promoter Variant Schwartz, David A; Blumhagen, Rachel Z; Fingerlin, Tasha E
American journal of respiratory and critical care medicine,
11/2022, Letnik:
206, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Evolution represents genetic adaptations to changing environmental conditions, and these genomic alterations frequently have both advantageous and unfavorable effects. Genetic alterations, or ...alleles, that give kids a survival benefit are more likely to be preserved and become more common. For instance, benefits brought about by positive selection might have to do with improved reproductive and/or early-life survival. Purifying selection can eliminate alleles from the population that are detrimental in various ways. However, due to their advantages in early life survival and/or reproduction, some genes that carry an elevated risk for a disease unrelated to offspring survival may be under positive selection. In those circumstances, positive selection has the effect of preventing a harmful genetic change that increases the likelihood of disease.
Idiopathic pulmonary fibrosis (IPF) is a heterogeneous disease that is pathologically characterized by areas of normal-appearing lung parenchyma, active fibrosis (transition zones including ...fibroblastic foci) and dense fibrosis. Defining transcriptional differences between these pathologically heterogeneous regions of the IPF lung is critical to understanding the distribution and extent of fibrotic lung disease and identifying potential therapeutic targets. Application of a spatial transcriptomics platform would provide more detailed spatial resolution of transcriptional signals compared to previous single cell or bulk RNA-Seq studies.
We performed spatial transcriptomics using GeoMx Nanostring Digital Spatial Profiling on formalin-fixed paraffin-embedded (FFPE) tissue from 32 IPF and 12 control subjects and identified 231 regions of interest (ROIs). We compared normal-appearing lung parenchyma and airways between IPF and controls with histologically normal lung tissue, as well as histologically distinct regions within IPF (normal-appearing lung parenchyma, transition zones containing fibroblastic foci, areas of dense fibrosis, and honeycomb epithelium metaplasia).
We identified 254 differentially expressed genes (DEGs) between IPF and controls in histologically normal-appearing regions of lung parenchyma; pathway analysis identified disease processes such as EIF2 signaling (important for cap-dependent mRNA translation), epithelial adherens junction signaling, HIF1α signaling, and integrin signaling. Within IPF, we identified 173 DEGs between transition and normal-appearing lung parenchyma and 198 DEGs between dense fibrosis and normal lung parenchyma; pathways dysregulated in both transition and dense fibrotic areas include EIF2 signaling pathway activation (upstream of endoplasmic reticulum (ER) stress proteins ATF4 and CHOP) and wound healing signaling pathway deactivation. Through cell deconvolution of transcriptome data and immunofluorescence staining, we confirmed loss of alveolar parenchymal signals (AGER, SFTPB, SFTPC), gain of secretory cell markers (SCGB3A2, MUC5B) as well as dysregulation of the upstream regulator ATF4, in histologically normal-appearing tissue in IPF.
Our findings demonstrate that histologically normal-appearing regions from the IPF lung are transcriptionally distinct when compared to similar lung tissue from controls with histologically normal lung tissue, and that transition zones and areas of dense fibrosis within the IPF lung demonstrate activation of ER stress and deactivation of wound healing pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
9.
Refractory neutrophilic asthma and ciliary genes Guntur, Vamsi P.; Manka, Laurie A.; Moore, Camille M. ...
Journal of allergy and clinical immunology,
June 2022, 2022-06-00, 20220601, Letnik:
149, Številka:
6
Journal Article
Recenzirano
Refractory asthma (RA) remains poorly controlled, resulting in high health care utilization despite guideline-based therapies. Patients with RA manifest higher neutrophilia as a result of increased ...airway inflammation and subclinical infection, the underlying mechanisms of which remain unclear.
We sought to characterize and clinically correlate gene expression differences between refractory and nonrefractory (NR) asthma to uncover molecular mechanisms driving group distinctions.
Microarray gene expression of paired airway epithelial brush and endobronchial biopsy samples was compared between 60 RA and 30 NR subjects. Subjects were hierarchically clustered to identify subgroups of RA, and biochemical and clinical traits (airway inflammatory molecules, respiratory pathogens, chest imaging) were compared between groups. Weighted gene correlation network analysis was used to identify coexpressed gene modules. Module expression scores were compared between groups using linear regression, controlling for age, sex, and body mass index.
Differential gene expression analysis showed upregulation of proneutrophilic and downregulation of ciliary function genes/pathways in RA compared to NR. A subgroup of RA with downregulated ciliary gene expression had increased levels of subclinical infections, airway neutrophilia, and eosinophilia as well as higher chest imaging mucus burden compared to other RA, the dominant differences between RA and NR. Weighted gene correlation network analysis identified gene modules related to ciliary function, which were downregulated in RA and were associated with lower pulmonary function and higher airway wall thickness/inflammation, markers of poorer asthma control.
Identification of a novel ciliary-deficient subgroup of RA suggests that diminished mucociliary clearance may underlie repeated asthma exacerbations despite adequate treatment, necessitating further exploration of function, mechanism, and therapeutics.
The effects of chronic inhaled and systemic corticosteroids use on COVID-19 susceptibility and severity are unclear. Since many patients with chronic pulmonary diseases rely on corticosteroids to ...control disease, it is important to understand the risks of their use during the pandemic. We aim to study if the use of inhaled or systemic corticosteroids affects the likelihood of developing COVID-19 infection.
We used the National Jewish Health electronic medical record research database to identify a cohort of all subjects who were tested for suspected COVID-19 between March 11 - June 23, 2020. Testing results, medication use, and comorbidities were obtained from the medical record. Following a comparison of different propensity score weighting methods, overlap propensity score weighting was used to analyze the association between medication use and COVID-19 diagnosis.
The cohort consisted of 928 patients, of which 12% tested positive. The majority (66%) of patients had a history of chronic pulmonary diseases. There was no significant association between inhaled corticosteroid use and testing positive for COVID-19. Interestingly, systemic corticosteroid use was associated with a lower odds ratio (0.95, 95% CI: 0.91–0.99) of testing positive for COVID-19. Similar results were noted when the analysis was restricted to those with any chronic pulmonary diseases, with asthma or with chronic obstructive pulmonary disease (COPD).
Our study supports the recommendation that patients with chronic pulmonary diseases, including asthma and COPD who require treatment with either inhaled or systemic corticosteroids, should continue their use during the COVID-19 pandemic.
•Systemic corticosteroids may lower the likelihood of testing positive for COVID-19.•An analysis of EMR using overlap propensity score weighting methods.•Patients with indications for corticosteroid therapy should continue using them.
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