Purpose of review
Systemic sclerosis (SSc) is heterogenous on molecular, cellular, tissue, and clinical levels. Although many biomarkers have been described in clinical studies, few have been ...rigorously mapped to specific molecular pathways, tissue pathologies, and clinical manifestations. A focused assessment of peripheral blood levels of C–C Motif Chemokine Ligand-18 (CCL18) and periostin illustrates how biomarkers can link molecular mediators to clinical outcomes.
Recent findings
CCL18 is produced by pulmonary macrophages in response to type 2 cytokines and IL6. Elevated serum CCL18 is associated with interstitial lung disease (ILD) in SSc patients and is prognostic for ILD progression. It is pharmacologically modulated by IL6 inhibition, and associated with stabilization of lung function decline but not with improvements in skin fibrosis. Periostin is produced by dermal fibroblasts in SSc in response to type 2 cytokines and transforming growth factor-beta. Elevated serum periostin is associated with cutaneous disease in SSc patients but not ILD. Other cell- and tissue-specific biomarkers detectable in peripheral blood and informative with respect to SSc pathogenesis include KL-6 and SP-D in lung epithelium, osteopontin in lung macrophages, and cartilage oligomeric matrix protein in dermal fibroblasts.
Summary
Blood biomarkers related to specific molecular mediators, cell types, and tissues of origin can help to link therapeutic targets to treatable traits in SSc.
Background Asthma is heterogeneous, and airway dysbiosis is associated with clinical features in patients with mild-to-moderate asthma. Whether similar relationships exist among patients with severe ...asthma is unknown. Objective We sought to evaluate relationships between the bronchial microbiome and features of severe asthma. Methods Bronchial brushings from 40 participants in the Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) study were evaluated by using 16S ribosomal RNA–based methods. Relationships to clinical and inflammatory features were analyzed among microbiome-profiled subjects. Secondarily, bacterial compositional profiles were compared between patients with severe asthma and previously studied healthy control subjects (n = 7) and patients with mild-to-moderate asthma (n = 41). Results In patients with severe asthma, bronchial bacterial composition was associated with several disease-related features, including body mass index ( P < .05, Bray-Curtis distance-based permutational multivariate analysis of variance; PERMANOVA), changes in Asthma Control Questionnaire (ACQ) scores ( P < .01), sputum total leukocyte values ( P = .06), and bronchial biopsy eosinophil values (per square millimeter, P = .07). Bacterial communities associated with worsening ACQ scores and sputum total leukocyte values (predominantly Proteobacteria) differed markedly from those associated with body mass index (Bacteroidetes/Firmicutes). In contrast, improving/stable ACQ scores and bronchial epithelial gene expression of FK506 binding protein (FKBP5) , an indicator of steroid responsiveness, correlated with Actinobacteria. Mostly negative correlations were observed between biopsy eosinophil values and Proteobacteria. No taxa were associated with a TH 2-related epithelial gene expression signature, but expression of TH 17-related genes was associated with Proteobacteria. Patients with severe asthma compared with healthy control subjects or patients with mild-to-moderate asthma were significantly enriched in Actinobacteria, although the largest differences observed involved a Klebsiella genus member (7.8-fold increase in patients with severe asthma, adjusted P < .001). Conclusions Specific microbiota are associated with and may modulate inflammatory processes in patients with severe asthma and related phenotypes. Airway dysbiosis in patients with severe asthma appears to differ from that observed in those with milder asthma in the setting of inhaled corticosteroid use.
Background Eosinophilic airway inflammation is heterogeneous in asthmatic patients. We recently described a distinct subtype of asthma defined by the expression of genes inducible by TH 2 cytokines ...in bronchial epithelium. This gene signature, which includes periostin, is present in approximately half of asthmatic patients and correlates with eosinophilic airway inflammation. However, identification of this subtype depends on invasive airway sampling, and hence noninvasive biomarkers of this phenotype are desirable. Objective We sought to identify systemic biomarkers of eosinophilic airway inflammation in asthmatic patients. Methods We measured fraction of exhaled nitric oxide (F eno ), peripheral blood eosinophil, periostin, YKL-40, and IgE levels and compared these biomarkers with airway eosinophilia in asthmatic patients. Results We collected sputum, performed bronchoscopy, and matched peripheral blood samples from 67 asthmatic patients who remained symptomatic despite maximal inhaled corticosteroid treatment (mean FEV1 , 60% of predicted value; mean Asthma Control Questionnaire ACQ score, 2.7). Serum periostin levels are significantly increased in asthmatic patients with evidence of eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. A logistic regression model, including sex, age, body mass index, IgE levels, blood eosinophil numbers, F eno levels, and serum periostin levels, in 59 patients with severe asthma showed that, of these indices, the serum periostin level was the single best predictor of airway eosinophilia ( P = .007). Conclusion Periostin is a systemic biomarker of airway eosinophilia in asthmatic patients and has potential utility in patient selection for emerging asthma therapeutics targeting TH 2 inflammation.
Periostin, also termed osteoblast-specific factor 2, is a matricellular protein with known functions in osteology, tissue repair, oncology, cardiovascular and respiratory systems, and in various ...inflammatory settings. However, most of the research to date has been conducted in divergent and circumscribed areas meaning that the overall understanding of this intriguing molecule remains fragmented. Here, we integrate the available evidence on periostin expression, its normal role in development, and whether it plays a similar function during pathologic repair, regeneration, and disease in order to bring together the different research fields in which periostin investigations are ongoing. In spite of the seemingly disparate roles of periostin in health and disease, tissue remodeling as a response to insult/injury is emerging as a common functional denominator of this matricellular molecule. Periostin is transiently upregulated during cell fate changes, either physiologic or pathologic. Combining observations from various conditions, a common pattern of events can be suggested, including periostin localization during development, insult and injury, epithelial–mesenchymal transition, extracellular matrix restructuring, and remodeling. We propose mesenchymal remodeling as an overarching role for the matricellular protein periostin, across physiology and disease. Periostin may be seen as an important structural mediator, balancing appropriate versus inappropriate tissue adaption in response to insult/injury.
Fibroblasts are non-haematopoietic structural cells that define the architecture of organs, support the homeostasis of tissue-resident cells and have key roles in fibrosis, cancer, autoimmunity and ...wound healing
. Recent studies have described fibroblast heterogeneity within individual tissues
. However, the field lacks a characterization of fibroblasts at single-cell resolution across tissues in healthy and diseased organs. Here we constructed fibroblast atlases by integrating single-cell transcriptomic data from about 230,000 fibroblasts across 17 tissues, 50 datasets, 11 disease states and 2 species. Mouse fibroblast atlases and a Dpt
knock-in mouse identified two universal fibroblast transcriptional subtypes across tissues. Our analysis suggests that these cells can serve as a reservoir that can yield specialized fibroblasts across a broad range of steady-state tissues and activated fibroblasts in disease. Comparison to an atlas of human fibroblasts from perturbed states showed that fibroblast transcriptional states are conserved between mice and humans, including universal fibroblasts and activated phenotypes associated with pathogenicity in human cancer, fibrosis, arthritis and inflammation. In summary, a cross-species and pan-tissue approach to transcriptomics at single-cell resolution has identified key organizing principles of the fibroblast lineage in health and disease.
Roles of Periostin in Respiratory Disorders Izuhara, Kenji; Conway, Simon J; Moore, Bethany B ...
American journal of respiratory and critical care medicine,
05/2016, Letnik:
193, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Periostin is a matricellular protein that has been implicated in many disease states. It interacts with multiple signaling cascades to modulate the expression of downstream genes that regulate ...cellular interactions within the extracellular matrix. This review focuses on the role of periostin in respiratory diseases, including asthma and idiopathic pulmonary fibrosis, and its potential to help guide treatment or assess prognosis. Epithelial injury is a common feature of many respiratory diseases, resulting in the secretion, among others, of periostin, which is subsequently involved in airway remodeling and other aspects of pulmonary pathophysiology. In asthma, periostin is recognized as a biomarker of type 2 inflammation; POSTN gene expression is up-regulated in bronchial epithelial cells by IL-13 and IL-4. Serum periostin has been evaluated for the identification of patients with increased clinical benefit from treatment with anti-IL-13 (lebrikizumab, tralokinumab) and anti-IgE (omalizumab) therapy and may be prognostic for increased risk of asthma exacerbations and progressive lung function decline. Furthermore, in asthma, periostin may regulate subepithelial fibrosis and mucus production and may serve as a systemic biomarker of eosinophilic airway inflammation. Periostin is also highly expressed in the lungs of patients with idiopathic pulmonary fibrosis, and its serum levels may predict clinical progression. Overall, periostin contributes to multiple pathogenic processes across respiratory diseases, and peripheral blood levels of periostin may have utility as a biomarker of treatment response and disease progression.
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial ...tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Background Biomarkers, preferably noninvasive, that predict asthma inception in children are lacking. Objective Little is known about biomarkers of type 2 inflammation in early life in relation to ...asthma inception. We evaluated aeroallergen sensitization, peripheral blood eosinophils, and serum periostin as potential biomarkers of asthma in children. Methods Children enrolled in the Childhood Origins of ASThma study were followed prospectively from birth. Blood samples were collected at ages 2, 4, 6, and 11 years, and serum-specific IgE levels, blood eosionophil counts, and periostin levels were measured in 244 children. Relationships among these biomarkers, age, and asthma were assessed. Results Serum periostin levels were approximately 2- to 3-fold higher in children than previously observed adult levels. Levels were highest at 2 years (145 ng/mL), and did not change significantly between 4 and 11 years (128 and 130 ng/mL). Age 2 year periostin level of 150 ng/mL or more predicted asthma at age 6 years (odds ratio OR, 2.3; 95% CI, 1.3-4.4). Eosinophil count of 300 cells/μL or more and aeroallergen sensitization at age 2 years were each associated with increased risk of asthma at age 6 years (OR, 3.1; 95% CI, 1.7-6.0 and OR, 3.3; 95% CI, 1.7-6.3). Children with any 2 of the biomarkers had a significantly increased risk of developing asthma by school age (≥2 biomarkers vs none: OR, 6.6; 95% CI, 2.7-16.0). Conclusions Serum periostin levels are significantly higher in children than in adults, likely due to bone turnover, which impairs clinical utility in children. Early life aeroallergen sensitization and elevated blood eosinophils are robust predictors of asthma development. Children with evidence of activation of multiple pathways of type 2 inflammation in early life are at greatest risk for asthma development.
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