S100A8/A9: a mediator of severe asthma pathogenesis and morbidity?This article is one of a selection of papers published in a special issue celebrating the 125th anniversary of the Faculty of Medicine at the University of Manitoba.

2009 ◽  
Vol 87 (10) ◽  
pp. 743-755 ◽  
Author(s):  
Andrew J. Halayko ◽  
Saeid Ghavami
Keyword(s):  
Airway Inflammation ◽  
Severe Asthma ◽  
Protein Complex ◽  
Airway Remodeling ◽  
Severe Disease ◽  
S100 Protein ◽  
Future Research ◽  
Inhaled Steroids ◽  
Molecular Pattern ◽  
125Th Anniversary

Nearly 12% of children and 6% of adults in Canada have been diagnosed with asthma. Although in most patients symptoms are controlled by inhaled steroids, a subpopulation (∼10%) characterized by excessive airway neutrophilia, is refractory to treatment; these patients exhibit severe disease, and account for more than 50% of asthma health care costs. These numbers underscore the need to better understand the biology of severe asthma and identify pro-asthma mediators released by cells, such as neutrophils, that are unresponsive to common steroid therapy. This review focuses on a unique protein complex consisting of S100A8 and S100A9. These subunits belong to the large Ca2+-binding S100 protein family and are some of the most abundant proteins in neutrophils and macrophages. S100A8/A9 is a damage-associated molecular pattern (DAMP) protein complex released in abundance in rheumatoid arthritis, inflammatory bowel disease, and cancer, but there are no definitive studies on its role in inflammation and obstructive airways disease. Two receptors for S100A8/A9, the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), are expressed in lung. TLR4 is linked with innate immunity that programs local airway inflammation, and RAGE participates in mediating fibroproliferative remodeling in idiopathic pulmonary fibrosis. S100A8/A9 can induce cell proliferation, or apoptosis, inflammation, collagen synthesis, and cell migration. We hypothesize that this capacity suggests S100A8/A9 could underpin chronic airway inflammation and airway remodeling in asthma by inducing effector responses of resident and infiltrating airway cells. This review highlights some key issues related to this hypothesis and provides a template for future research.

scholarly journals Regulation of IL-17A and implications for TGF-β1 comodulation of airway smooth muscle remodeling in severe asthma

2019 ◽  
Vol 316 (5) ◽  
pp. L843-L868 ◽  
Author(s):  
Jon M. Evasovic ◽  
Cherie A. Singer
Keyword(s):  
Smooth Muscle ◽  
Airway Inflammation ◽  
Severe Asthma ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Airway Remodeling ◽  
High Dose ◽  
Persistent Symptoms ◽  
Immune Factors ◽  
Tgf Β1

Severe asthma develops as a result of heightened, persistent symptoms that generally coincide with pronounced neutrophilic airway inflammation. In individuals with severe asthma, symptoms are poorly controlled by high-dose inhaled glucocorticoids and often lead to elevated morbidity and mortality rates that underscore the necessity for novel drug target identification that overcomes limitations in disease management. Many incidences of severe asthma are mechanistically associated with T helper 17 (TH17) cell-derived cytokines and immune factors that mediate neutrophilic influx to the airways. TH17-secreted interleukin-17A (IL-17A) is an independent risk factor for severe asthma that impacts airway smooth muscle (ASM) remodeling. TH17-derived cytokines and diverse immune mediators further interact with structural cells of the airway to induce pathophysiological processes that impact ASM functionality. Transforming growth factor-β1 (TGF-β1) is a pivotal mediator involved in airway remodeling that correlates with enhanced TH17 activity in individuals with severe asthma and is essential to TH17 differentiation and IL-17A production. IL-17A can also reciprocally enhance activation of TGF-β1 signaling pathways, whereas combined TH1/TH17 or TH2/TH17 immune responses may additively impact asthma severity. This review seeks to provide a comprehensive summary of cytokine-driven T cell fate determination and TH17-mediated airway inflammation. It will further review the evidence demonstrating the extent to which IL-17A interacts with various immune factors, specifically TGF-β1, to contribute to ASM remodeling and altered function in TH17-driven endotypes of severe asthma.

scholarly journals Advances and Challenges of Antibody Therapeutics for Severe Bronchial Asthma

2021 ◽  
Vol 23 (1) ◽  
pp. 83
Author(s):  
Yuko Abe ◽  
Yasuhiko Suga ◽  
Kiyoharu Fukushima ◽  
Hayase Ohata ◽  
Takayuki Niitsu ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Severe Asthma ◽  
Airway Hyperresponsiveness ◽  
Airway Remodeling ◽  
Disease Process ◽  
Antibody Treatment ◽  
Airway Narrowing ◽  
Antibody Therapeutics ◽  
Phenotype Classification ◽  
Major Factors

Asthma is a disease that consists of three main components: airway inflammation, airway hyperresponsiveness, and airway remodeling. Persistent airway inflammation leads to the destruction and degeneration of normal airway tissues, resulting in thickening of the airway wall, decreased reversibility, and increased airway hyperresponsiveness. The progression of irreversible airway narrowing and the associated increase in airway hyperresponsiveness are major factors in severe asthma. This has led to the identification of effective pharmacological targets and the recognition of several biomarkers that enable a more personalized approach to asthma. However, the efficacies of current antibody therapeutics and biomarkers are still unsatisfactory in clinical practice. The establishment of an ideal phenotype classification that will predict the response of antibody treatment is urgently needed. Here, we review recent advancements in antibody therapeutics and novel findings related to the disease process for severe asthma.

scholarly journals PRMT5 in T cells drives Th17 responses, mixed granulocytic inflammation and severe allergic airway inflammation

2021 ◽  
Author(s):  
Brandon W Lewis ◽  
Stephanie A Amici ◽  
Hye-Young Kim ◽  
Emily Shalosky ◽  
Aiman Khan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Airway Inflammation ◽  
Severe Asthma ◽  
Lung Inflammation ◽  
Airway Remodeling ◽  
Symptom Control ◽  
Hospital Costs ◽  
Allergic Airway Inflammation ◽  
Arginine Methylation

Severe asthma is characterized by steroid insensitivity and poor symptom control, and is responsible for the majority of asthma-related hospital costs. Therapeutic options remain limited, in part due to a lack of mechanisms driving severe asthma phenotypes. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in asthmatic lungs. Here, we show that PRMT5 drives allergic airway inflammation in a mouse model reproducing multiple aspects of human severe asthma. We find that PRMT5 is required in CD4+ T cells for chronic steroid-insensitive severe lung inflammation, with selective T cell deletion of PRMT5 robustly suppressing eosinophilic and granulocytic lung inflammation, pathology, airway remodeling and hyperresponsiveness. Mechanistically, we observed high pulmonary sterol metabolic activity, ROR-γt and Th17 responses, with PRMT5-dependent increases in ROR-γt agonist desmosterol. Our work demonstrates that T cell PRMT5 drives severe allergic lung inflammation and has potential implications for the pathogenesis and therapeutic targeting of severe asthma.

Biologic Therapy and Asthma

2018 ◽  
Vol 39 (01) ◽  
pp. 100-114 ◽  
Author(s):  
Ravi Viswanathan ◽  
William Busse
Keyword(s):  
Airway Inflammation ◽  
Asthma Control ◽  
Severe Asthma ◽  
Clinical Characteristics ◽  
Biologic Therapy ◽  
Severe Disease ◽  
Asthma Patient ◽  
Clinical Heterogeneity ◽  
Patient Responsiveness

AbstractAlthough airway inflammation is an intrinsic and key feature of asthma, this response varies in its intensity and translation to clinical characteristics and responsiveness to treatment. The observations that clinical heterogeneity is an important aspect of asthma and a feature that likely dictates and determines responses to treatment in severe asthma, patient responsiveness to medication is incomplete, and risks for exacerbation are increased. The development of biologics, which target selected and specific components of inflammation, has been a promising advance to achieve asthma control in patients with severe disease. This article reviews the current biologics available and under development and how their use has affected asthma and which subpopulations appear to benefit the greatest.

scholarly journals Differences in airway remodeling and airway inflammation among moderate-severe asthma clinical phenotypes

2017 ◽  
Vol 9 (9) ◽  
pp. 2904-2914 ◽  
Author(s):  
Wen-Jing Ye ◽  
Wei-Guo Xu ◽  
Xue-Jun Guo ◽  
Feng-Feng Han ◽  
Juan Peng ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Severe Asthma ◽  
Airway Remodeling ◽  
Clinical Phenotypes

Applying personalized medicine to adult severe asthma

2021 ◽  
Vol 42 (1) ◽  
pp. e8-e16 ◽  
Author(s):  
Angelica Tiotiu
Keyword(s):  
Personalized Medicine ◽  
Severe Asthma ◽  
Negative Impact ◽  
Target Therapy ◽  
Asthma Management ◽  
Future Research ◽  
Biologic Therapies ◽  
Eosinophilic Asthma ◽  
Definition Of ◽  
Structured Approach

Background: Severe asthma is a heterogeneous disease that consists of various phenotypes driven by different pathways. Associated with significant morbidity, an important negative impact on the quality of life of patients, and increased health care costs, severe asthma represents a challenge for the clinician. With the introduction of various antibodies that target type 2 inflammation (T2) pathways, severe asthma therapy is gradually moving to a personalized medicine approach. Objective: The purpose of this review was to emphasize the important role of personalized medicine in adult severe asthma management. Methods: An extensive research was conducted in medical literature data bases by applying terms such as “severe asthma” associated with “structured approach,” “comorbidities,” “biomarkers,” “phenotypes/endotypes,” and “biologic therapies.” Results: The management of severe asthma starts with a structured approach to confirm the diagnosis, assess the adherence to medications and identify confounding factors and comorbidities. The definition of phenotypes or endotypes (phenotypes defined by mechanisms and identified through biomarkers) is an important step toward the use of personalized medicine in asthma. Severe allergic and nonallergic eosinophilic asthma are two defined T2 phenotypes for which there are efficacious targeted biologic therapies currently available. Non-T2 phenotype remains to be characterized, and less efficient target therapy exists. Conclusion: Despite important progress in applying personalized medicine to severe asthma, especially in T2 inflammatory phenotypes, future research is needed to find valid biomarkers predictive for the response to available biologic therapies to develop more effective therapies in non-T2 phenotype.

scholarly journals Immunologic Pathophysiology and Airway Remodeling Mechanism in Severe Asthma: Focused on IgE-Mediated Pathways

Diagnostics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 83
Author(s):  
Shih-Lung Cheng
Keyword(s):  
Severe Asthma ◽  
Immunoglobulin E ◽  
Airway Remodeling ◽  
Real Life ◽  
Allergic Diseases ◽  
Proinflammatory Mediators ◽  
Small Subgroup ◽  
Humanized Monoclonal Antibody ◽  
Severe Allergic Asthma ◽  
Ige Mediated

Despite the expansion of the understanding in asthma pathophysiology and the continual advances in disease management, a small subgroup of patients remains partially controlled or refractory to standard treatments. Upon the identification of immunoglobulin E (IgE) and other inflammatory mediators, investigations and developments of targeted agents have thrived. Omalizumab is a humanized monoclonal antibody that specifically targets the circulating IgE, which in turn impedes and reduces subsequent releases of the proinflammatory mediators. In the past decade, omalizumab has been proven to be efficacious and well-tolerated in the treatment of moderate-to-severe asthma in both trials and real-life studies, most notably in reducing exacerbation rates and corticosteroid use. While growing evidence has demonstrated that omalizumab may be potentially beneficial in treating other allergic diseases, its indication remains confined to treating severe allergic asthma and chronic idiopathic urticaria. Future efforts may be bestowed on determining the optimal length of omalizumab treatment, seeking biomarkers that could better predict treatment response and as well as extending its indications.

scholarly journals Immunoregulation and antidepressant effect of ketamine

2021 ◽  
Vol 12 (1) ◽  
pp. 218-236
Author(s):  
Nan Zhang ◽  
Lihua Yao ◽  
Peilin Wang ◽  
Zhongchun Liu
Keyword(s):  
Disease Burden ◽  
Severe Disease ◽  
Mental Health Disorder ◽  
Antagonistic Effect ◽  
Antidepressant Effect ◽  
Future Research ◽  
Recurrence Rates ◽  
Aspartate Receptor ◽  
Antidepressant Effects ◽  
Common Mental Health Disorder

Abstract Major depressive disorder (MDD) is a common mental health disorder that brings severe disease burden worldwide. Traditional antidepressants are mainly targeted at monoamine neurotransmitters, with low remission rates and high recurrence rates. Ketamine is a noncompetitive glutamate N-methyl-d-aspartate receptor (NMDAR) antagonist, and its rapid and powerful antidepressant effects have come to light. Its antidepressant mechanism is still unclarified. Research found that ketamine had not only antagonistic effect on NMDAR but also strong immunomodulatory effect, both of which were closely related to the pathophysiology of MDD. Although there are many related studies, they are relatively heterogeneous. Therefore, this review mainly describes the immune mechanisms involved in MDD and how ketamine plays an antidepressant role by regulating peripheral and central immune system, including peripheral inflammatory cytokines, central microglia, and astrocytes. This review summarizes the related research, finds out the deficiencies of current research, and provides ideas for future research and the development of novel antidepressants.

scholarly journals FSTL1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Liu ◽  
Jiawei Xu ◽  
Tian Liu ◽  
Jinxiang Wu ◽  
Jiping Zhao ◽  
...  
Keyword(s):  
Lung Function ◽  
Airway Inflammation ◽  
Cigarette Smoke ◽  
Airway Remodeling ◽  
Critical Factor ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Impaired Lung Function

Abstract Background Cigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). Follistatin-like protein 1 (FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling. Methods Serum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1± mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA), an inhibitor of autophagy, was applied in CS-exposed WT mice. The lung tissues and serum from patients and murine models were tested for FSTL1 and autophagy-associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed using electron microscope technology. LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined using ELISA. Airway remodeling and lung function were also assessed. Results Both FSTL1 and autophagy biomarkers increased in COPD patients and CS-exposed WT mice. Autophagy activation was upregulated in CS-exposed mice accompanied by airway remodeling and airway inflammation. FSTL1± mice showed a lower level of CS-induced autophagy compared with the control mice. FSTL1± mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS-exposed WT mice with 3-MA pretreatment have a similar manifestation with CS-exposed FSTL1± mice. Conclusions FSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke-induced COPD.

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