Gfi1 controls the formation of effector CD8 T cells during chronic infection and cancer.

During chronic infections and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to Ly108 - CX3CR1 + effector-like cells. Generation of these effector-like cells is essential for the control of chronic infections and tumors, albeit limited. However, the precise cues and mechanisms directing the formation and maintenance of exhausted effector-like are incompletely understood. Using genetic mouse models challenged with LCMV Clone 13 or syngeneic tumors, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in exhausted CD8 T cells, which in turn regulates the formation of exhausted effector-like cells. Gfi1 deletion in T cells dysregulates the chromatin accessibility and transcriptomic programs associated with the differentiation of LCMV Clone 13-specific CD8 T cell exhaustion, preventing the formation of effector-like and terminally exhausted cells while maintaining progenitors and a newly identified Ly108 + CX3CR1 + state. These Ly108 + CX3CR1 + cells have a distinct chromatin profile and may represent an alternative target for therapeutic interventions to combat chronic infections and cancer. In sum, we show that Gfi1 is a critical regulator of the formation of exhausted effector-like cells.

Blood donation screening for hepatitis B virus core antibodies: The importance of confirmatory testing and initial implication for rare blood donor groups.

BACKGROUND AND OBJECTIVES: Exclusion of blood donors with hepatitis B virus (HBV) core antibodies (anti-HBc) prevents transfusion-transmitted HBV infection but can lead to significant donor loss. As isolated anti-HBc positivity does not always indicate true past HBV infection, we have investigated the effectiveness of confirmatory anti-HBc testing and the representation of rare blood groups in anti-HBc-positive donors. MATERIALS AND METHODS: Three hundred ninety-seven HBV surface antigen-negative and anti-HBc initially reactive blood donor samples were tested by five different anti-HBc assays. RESULTS: Eighty percentage of samples reactive in Architect anti-HBc assay were positive by the Murex assay and anti-HBc neutralization. Eleven out of 397 samples showed discordant results in supplementary testing from the Murex confirmatory test result, and five remained undetermined following extensive serological testing. Thirty-eight percentage of anti-HBc-positive donors identified as minority ethnic groups compared with 11% representation in anti-HBc-negative donors (p < 0.0001); the frequency of the Ro blood group in anti-HBc-positive donors was 18 times higher in non-white ethnic groups. CONCLUSION: Using two anti-HBc assays effectively enabled the identification of HBV-exposed and potentially infectious donors, their deferral and potential clinical follow-up. However, the exclusion of confirmed anti-HBc-positive donors will still impact the supply of rare blood such as Ro.

Short-term cardiovascular events after bariatric surgery in patients with metabolic syndrome.

BACKGROUND: Patients with metabolic syndrome (MetS) are at increased risk of developing cardiovascular disease along with other adverse events after bariatric surgery. OBJECTIVES: The incidence of short-term major adverse cardiovascular events (MACE) in patients with MetS undergoing bariatric surgery is not well characterized. SETTING: Accredited bariatric surgery centers in the United States and Canada. METHODS: A total of 760,076 patients aged ≥18 years with body mass index ≥35 kg/m2 who underwent primary bariatric surgery between 2015 and 2018 were included. Patients with both diabetes and hypertension were described as the MetS cohort. Patient characteristics, operative technique, and 30-day outcomes were compared. The primary outcome was incidence of MACE, a composite of myocardial infarction, stroke, and all-cause mortality. Unadjusted and multivariable logistic regression analyses were performed and included an interaction between MetS and hyperlipidemia (HLD). RESULTS: Of the 577,882 patients included, 111,128 (19.2%) exhibited MetS. Patients with MetS more frequently experienced MACE compared with patients without MetS (.3% versus .1%; P < .001). The odds of MACE were greater for patients with MetS versus Non-MetS (odds ratio [OR] 2.87; 95% CI, 2.49-3.32) in the unadjusted analysis. MetS without HLD, MetS with HLD, and Non-MetS with HLD are significantly associated with MACE when compared with those with non-MetS without HLD. CONCLUSIONS: Patients with MetS have an increased frequency of cardiac events following bariatric surgery. Future studies should determine if optimization of 1 or more components of MetS or other related co-morbidities reduces the cardiovascular risk for patients.

Corrigendum: Quantification of joint mobility limitation in adult type 1 diabetes.

[This corrects the article DOI: 10.3389/fendo.2023.1238825.].

Quantification of joint mobility limitation in adult type 1 diabetes.

Aims: Diabetic cheiroarthropathies limit hand mobility due to fibrosis and could be markers of a global profibrotic trajectory. Heterogeneity in definitions and lack of a method to measure it complicate studying associations with organ involvement and treatment outcomes. We measured metacarpophalangeal (MCP) joint extension as a metric and describe magnetic resonance (MR) imaging determinants of MCP restriction. Methods: Adults with type 1 diabetes were screened for hand manifestations using a symptom questionnaire, clinical examination, and function [Duruoz hand index (DHI) and grip strength]. Patients were segregated by mean MCP extension (<20°, 20°-40°, 40°-60°, and >60°) for MR imaging (MRI) scanning. Patients in the four groups were compared using ANOVA for clinical features and MRI tissue measurements (tenosynovial, skin, and fascia thickness). We performed multiple linear regression for determinants of MCP extension. Results: Of the 237 patients (90 men), 79 (33.8%) with cheiroarthropathy had MCP extension limitation (39° versus 61°, p < 0.01). Groups with limited MCP extension had higher DHI (1.9 vs. 0.2) but few (7%) had pain. Height, systolic blood pressure, and nephropathy were associated with mean MCP extension. Hand MRI (n = 61) showed flexor tenosynovitis in four patients and median neuritis in one patient. Groups with MCP mobility restriction had the thickest palmar skin; tendon thickness or median nerve area did not differ. Only mean palmar skin thickness was associated with MCP extension angle on multiple linear regression. Conclusion: Joint mobility limitation was quantified by restricted mean MCP extension and had structural correlates on MRI. These can serve as quantitative measures for future associative and interventional studies.

Does hand stiffness reflect internal organ fibrosis in diabetes mellitus?

Fibrosis leads to irreversible stiffening of tissue and loss of function, and is a common pathway leading to morbidity and mortality in chronic disease. Diabetes mellitus (both type 1 and type 2 diabetes) are associated with significant fibrosis in internal organs, chiefly the kidney and heart, but also lung, liver and adipose tissue. Diabetes is also associated with the diabetic cheirarthropathies, a collection of clinical manifestations affecting the hand that include limited joint mobility (LJM), flexor tenosynovitis, Duypuytren disease and carpal tunnel syndrome. Histo-morphologically these are profibrotic conditions affecting various soft tissue components in the hand. We hypothesize that these hand manifestations reflect a systemic profibrotic state, and are potential clinical biomarkers of current or future internal organ fibrosis. Epidemiologically, there is evidence that fibrosis in one organ associates with fibrosis with another; the putative exposures that lead to fibrosis in diabetes (advanced glycation end product deposition, microvascular disease and hypoxia, persistent innate inflammation) are 'systemic'; a common genetic susceptibility to fibrosis has also been hinted at. These data suggest that a subset of the diabetic population is susceptible to multi-organ fibrosis. The hand is an attractive biomarker to clinically detect this susceptibility, owing to its accessibility to physical examination and exposure to repeated mechanical stresses. Testing the hypothesis has a few pre-requisites: being able to measure hand fibrosis in the hand, using clinical scores or imaging based scores, which will facilitate looking for associations with internal organ fibrosis using validated methodologies for each. Longitudinal studies would be essential in delineating fibrosis trajectories in those with hand manifestations. Since therapies reversing fibrosis are few, the onus lies on identification of a susceptible subset for preventative measures. If systematically validated, clinical hand examination could provide a low-cost, universally accessible and easily reproducible screening step in selecting patients for clinical trials for fibrosis in diabetes.

Effects of Oxidative Stress on Airway Epithelium Permeability in Asthma and Potential Implications for Patients with Comorbid Obesity.

20 million adults and 4.2 million children in the United States have asthma, a disease resulting in inflammation and airway obstruction in response to various factors, including allergens and pollutants and nonallergic triggers. Obesity, another highly prevalent disease in the US, is a major risk factor for asthma and a significant cause of oxidative stress throughout the body. People with asthma and comorbid obesity are susceptible to developing severe asthma that cannot be sufficiently controlled with current treatments. More research is needed to understand how asthma pathobiology is affected when the patient has comorbid obesity. Because the airway epithelium directly interacts with the outside environment and interacts closely with the immune system, understanding how the airway epithelium of patients with asthma and comorbid obesity is altered compared to that of lean asthma patients will be crucial for developing more effective treatments. In this review, we discuss how oxidative stress plays a role in two chronic inflammatory diseases, obesity and asthma, and propose a mechanism for how these conditions may compromise the airway epithelium.

Vertical sleeve gastrectomy associates with airway hyperresponsiveness in a murine model of allergic airway disease and obesity.

Introduction: Asthma is a chronic airway inflammatory disease marked by airway inflammation, remodeling and hyperresponsiveness to allergens. Allergic asthma is normally well controlled through the use of beta-2-adrenergic agonists and inhaled corticosteroids; however, a subset of patients with comorbid obesity experience resistance to currently available therapeutics. Patients with asthma and comorbid obesity are also at a greater risk for severe disease, contributing to increased risk of hospitalization. Bariatric surgery improves asthma control and airway hyperresponsiveness in patients with asthma and comorbid obesity, however, the underlying mechanisms for these improvements remain to be elucidated. We hypothesized that vertical sleeve gastrectomy (VSG), a model of metabolic surgery in mice, would improve glucose tolerance and airway inflammation, resistance, and fibrosis induced by chronic allergen challenge and obesity. Methods: Male C57BL/6J mice were fed a high fat diet (HFD) for 13 weeks with intermittent house dust mite (HDM) allergen administration to induce allergic asthma, or saline as control. At week 11, a subset of mice underwent VSG or Sham surgery with one week recovery. A separate group of mice did not undergo surgery. Mice were then challenged with HDM or saline along with concurrent HFD feeding for 1-1.5 weeks before measurement of lung mechanics and harvesting of tissues, both of which occurred 24 hours after the final HDM challenge. Systemic and pulmonary cytokine profiles, lung histology and gene expression were analyzed. Results: High fat diet contributed to increased body weight, serum leptin levels and development of glucose intolerance for both HDM and saline treatment groups. When compared to saline-treated mice, HDM-challenged mice exhibited greater weight gain. VSG improved glucose tolerance in both saline and HDM-challenged mice. HDM-challenged VSG mice exhibited an increase in airway hyperresponsiveness to methacholine when compared to the non-surgery group. Discussion: The data presented here indicate increased airway hyperresponsiveness in allergic mice undergoing bariatric surgery.

Allergic Asthma Responses Are Dependent on Macrophage Ontogeny.

The ontogenetic composition of tissue-resident macrophages following injury, environmental exposure, or experimental depletion can be altered upon re-establishment of homeostasis. However, the impact of altered resident macrophage ontogenetic milieu on subsequent immune responses is poorly understood. Hence, we assessed the effect of macrophage ontogeny alteration following return to homeostasis on subsequent allergic airway responses to house dust mites (HDM). Using lineage tracing, we confirmed alveolar and interstitial macrophage ontogeny and their replacement by bone marrow-derived macrophages following LPS exposure. This alteration in macrophage ontogenetic milieu reduced allergic airway responses to HDM challenge. In addition, we defined a distinct population of resident-derived interstitial macrophages expressing allergic airway disease genes, located adjacent to terminal bronchi, and reduced by prior LPS exposure. These findings support that the ontogenetic milieu of pulmonary macrophages is a central factor in allergic airway responses and has implications for how prior environmental exposures impact subsequent immune responses and the development of allergy.

Effects of biological therapies on patients with Type-2 high asthma and comorbid obesity.

Over 20 million adults and 6 million children in the United States (US) have asthma, a chronic respiratory disease characterized by airway inflammation, bronchoconstriction, and mucus hypersecretion. Obesity, another highly prevalent disease in the US, is a major risk factor for asthma and a significant cause of diminished asthma control, increased submucosal eosinophilia, and reduced quality of life. A large subgroup of these patients experiences severe symptoms and recurrent exacerbations despite maximal dosage of standard asthma therapies. In the past two decades, the development of biological therapies has revolutionized the field and advanced our understanding of type 2 inflammatory biomarkers. However, patients with obesity and comorbid asthma are not principally considered in clinical trials of biologics. Large landmark cluster analyses of patients with asthma have consistently identified specific asthma phenotypes that associate with obesity but may be differentiated by age of asthma onset and inflammatory cell profiles in sputum. These patterns suggest that biologic processes driving asthma pathology are heterogenous among patients with obesity. The biological mechanisms driving pathology in patients with asthma and comorbid obesity are not well understood and likely multifactorial. Future research needs to be done to elicit the cellular and metabolic functions in the relationship of obesity and asthma to yield the best treatment options for this multiplex condition. In this review, we explore the key features of type 2 inflammation in asthma and discuss the effectiveness, safety profile, and research gaps regarding the currently approved biological therapies in asthma patients with obesity.

A Retrospective Real-World Study of the Effectiveness and Tolerability of Tildrakizumab in UK Adults with Moderate-to-Severe Chronic Plaque Psoriasis.

INTRODUCTION: As with most medicines historically, clinicians prescribing tildrakizumab have relied on information derived from registration studies undertaken in a prospective controlled clinical trial setting. More recently, clinicians, policymakers, and commissioners increasingly rely on real-world data to inform both policy and practice. METHODS: A retrospective real-world data study was undertaken at four specialist dermatology departments in the United Kingdom. All adult patients treated with tildrakizumab for moderate-to-severe plaque psoriasis were included, with data being collected for 122 patients. RESULTS: Psoriatic patients on tildrakizumab tended to be overweight (median body mass index of 32 (range 19-59) (n = 61); 26/68 (38%) < 90 kg, 32/68 (47%) between 90 and 120 kg, and 10/68 (15%) > 120 kg). The study population had high levels of comorbidities (83/116, 72%), multiple special sites (39/117, 33%), and histories of biological treatments (81/100, 81%). Most patients (61/80, 76%) initiated on tildrakizumab were switched from another biological treatment. Tildrakizumab was effective, with 91/122 (75%) patients remaining on treatment for the duration of the study-a median of 12 months per patient (range 1-29 months)-and achieving a change in median Psoriasis Area and Severity Index (PASI) from 12 to 0.35 and in Dermatology Life Quality Index (DLQI) from 20 to 0. The response rate was 57/66 (86%) when tildrakizumab was used as the first- or second-line biologic compared to 19/31 (61%) when used as the third- to seventh-line. Thirty-three (78.6%) patients over 90 kg of weight received the 200-mg dose of tildrakizumab. All but one (n = 8) patient with body weight over 120 kg maintained response over time. There was one treatment discontinuation; a patient who had a local sensitivity reaction. CONCLUSIONS: In UK clinical practice, tildrakizumab was well tolerated and effective at doses of 100 mg or 200 mg in a range of patient phenotypes.

3'UTR shortening of HAS2 promotes hyaluronan hyper-synthesis and bioenergetic dysfunction in pulmonary hypertension.

Pulmonary hypertension (PH) comprises a diverse group of disorders that share a common pathway of pulmonary vascular remodeling leading to right ventricular failure. Development of anti-remodeling strategies is an emerging frontier in PH therapeutics that requires a greater understanding of the interactions between vascular wall cells and their extracellular matrices. The ubiquitous matrix glycan, hyaluronan (HA), is markedly elevated in lungs from patients and experimental models with PH. Herein, we identified HA synthase-2 (HAS2) in the pulmonary artery smooth muscle cell (PASMC) layer as a predominant locus of HA dysregulation. HA upregulation involves depletion of NUDT21, a master regulator of alternative polyadenylation, resulting in 3'UTR shortening and hyper-expression of HAS2. The ensuing increase of HAS2 and hyper-synthesis of HA promoted bioenergetic dysfunction of PASMC characterized by impaired mitochondrial oxidative capacity and a glycolytic shift. The resulting HA accumulation stimulated pro-remodeling phenotypes such as cell proliferation, migration, apoptosis-resistance, and stimulated pulmonary artery contractility. Transgenic mice, mimicking HAS2 hyper-synthesis in smooth muscle cells, developed spontaneous PH, whereas targeted deletion of HAS2 prevented experimental PH. Pharmacological blockade of HAS2 restored normal bioenergetics in PASMC, ameliorated cell remodeling phenotypes, and reversed experimental PH in vivo. In summary, our results uncover a novel mechanism of HA hyper-synthesis and downstream effects on pulmonary vascular cell metabolism and remodeling.

Exogenous leptin enhances markers of airway fibrosis in a mouse model of chronic allergic airways disease.

BACKGROUND: Asthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis. METHODS: Five-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6-9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson's trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated. RESULTS: Leptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice. CONCLUSIONS: In HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females.

Improving dementia care: insights from audit and feedback in interdisciplinary primary care sites.

BACKGROUND: Many primary care sites have implemented models to improve detection, diagnosis, and management of dementia, as per Canadian guidelines. The aim of this study is to describe the responses of clinicians, managers, and staff of sites that have implemented these models when presented with audit results, their insights on the factors that explain their results, their proposed solutions for improvement and how these align to one another. METHODS: One audit and feedback cycle was carried out in eight purposefully sampled sites in Ontario, Canada, that had previously implemented dementia care models. Audit consisted of a) chart review to assess quality of dementia care indicators, b) questionnaire to assess the physicians' knowledge, attitudes and practice toward dementia care, and c) semi-structured interviews to understand barriers and facilitators to implementing these models. Feedback was given to clinicians, managers, and staff in the form of graphic and oral presentations, followed by eight focus groups (one per site). Discussions revolved around: what audit results elicited more discussion from the participants, 2) their insights on the factors that explain their audit results, and 3) solutions they propose to improve dementia care. Deductive content and inductive thematic analyses, grounded in causal pathways models' theory was performed. FINDINGS: The audit and feedback process allowed the 63 participants to discuss many audit results and share their insights on a) organizational factors (lack of human resources, the importance of organized links with community services, clear roles and support from external memory clinics) and b) clinician factors (perceived competency practice and attitudes on dementia care), that could explain their audit results. Participants also provided solutions to improve dementia care in primary care (financial incentives, having clear pathways, adding tools to improve chart documentation, establish training on dementia care, and the possibility of benchmarking with other institutions). Proposed solutions were well aligned with their insights and further nuanced according to contextual details. CONCLUSIONS: This study provides valuable information on solutions proposed by primary care clinicians, managers, and staff to improve dementia care in primary care. The solutions are grounded in clinical experience and will inform ongoing and future dementia strategies.

Intrinsic IL-2 production by effector CD8 T cells affects IL-2 signaling and promotes fate decisions, stemness, and protection.

Here, we show that the capacity to manufacture IL-2 identifies constituents of the expanded CD8 T cell effector pool that display stem-like features, preferentially survive, rapidly attain memory traits, resist exhaustion, and control chronic viral challenges. The cell-intrinsic synthesis of IL-2 by CD8 T cells attenuates the ability to receive IL-2-dependent STAT5 signals, thereby limiting terminal effector formation, endowing the IL-2-producing effector subset with superior protective powers. In contrast, the non-IL-2-producing effector cells respond to IL-2 signals and gain effector traits at the expense of memory formation. Despite having distinct properties during the effector phase, IL-2-producing and nonproducing CD8 T cells appear to converge transcriptionally as memory matures to form populations with equal recall abilities. Therefore, the potential to produce IL-2 during the effector, but not memory stage, is a consequential feature that dictates the protective capabilities of the response.

Tfh-cell-derived interleukin 21 sustains effector CD8+ T cell responses during chronic viral infection.

CD4+ T cell-derived interleukin 21 (IL-21) sustains CD8+ T cell responses during chronic viral infection, but the helper subset that confers this protection remains unclear. Here, we applied scRNA and ATAC-seq approaches to determine the heterogeneity of IL-21+CD4+ T cells during LCMV clone 13 infection. CD4+ T cells were comprised of three transcriptionally and epigenetically distinct populations: Cxcr6+ Th1 cells, Cxcr5+ Tfh cells, and a previously unrecognized Slamf6+ memory-like (Tml) subset. T cell differentiation was specifically redirected toward the Tml subset during chronic, but not acute, LCMV infection. Although this subset displayed an enhanced capacity to accumulate and some developmental plasticity, it remained largely quiescent, which may hinder its helper potential. Conversely, mixed bone marrow chimera experiments revealed that Tfh cell-derived IL-21 was critical to sustain CD8+ T cell responses and viral control. Thus, strategies that bolster IL-21+Tfh cell responses may prove effective in enhancing CD8+ T cell-mediated immunity.

Imbalanced Coagulation in the Airway of Type-2 High Asthma with Comorbid Obesity.

Asthma is a common, chronic airway inflammatory disease marked by airway hyperresponsiveness, inflammation, and remodeling. Asthma incidence has increased rapidly in the past few decades and recent multicenter analyses have revealed several unique asthma endotypes. Of these, type-2 high asthma with comorbid obesity presents a unique clinical challenge marked by increased resistance to standard therapies and exacerbated disease development. The extrinsic coagulation pathway plays a significant role in both type-2 high asthma and obesity. The type-2 high asthma airway is marked by increased procoagulant potential, which is readily activated following damage to airway tissue. In this review, we summarize the current understanding of the role the extrinsic coagulation pathway plays in the airway of type-2 high asthma with comorbid obesity. We propose that asthma control is worsened in obesity as a result of a systemic and local airway shift towards a procoagulant and anti-fibrinolytic environment. Lastly, we hypothesize bariatric surgery as a treatment for improved asthma management in type-2 high asthma with comorbid obesity, facilitated by normalization of systemic procoagulant and pro-inflammatory mediators. A better understanding of attenuated coagulation parameters in the airway following bariatric surgery will advance our knowledge of biomolecular pathways driving asthma pathobiology in patients with obesity.

The Gut/Lung Microbiome Axis in Obesity, Asthma, and Bariatric Surgery: A Literature Review.

Mounting evidence suggests that obesity, parameters of metabolic syndrome, and asthma are significantly associated. Interestingly, these conditions are also associated with microbiome dysbiosis, notably in the airway microbiome for patients with asthma and in the gut microbiome for patients with obesity and/or metabolic syndrome. Considering that improvements in asthma control, lung function, and airway hyperresponsiveness are often reported after bariatric surgery, this review investigated the potential role of bacterial gut and airway microbiome changes after bariatric surgery in ameliorating asthma symptoms. Rapid and persistent gut microbiota alterations were reported following surgery, some of which can be sustained for years. The gut microbiome is thought to modulate airway cellular responses via short-chain fatty acids and inflammatory mediators, such that increased propionate and butyrate levels following surgery may aid in reducing asthma symptoms. In addition, increased prevalence of Akkermansia muciniphila after Roux-en-Y gastric bypass and sleeve gastrectomy may confer protection against airway hyperreactivity and inflammation. Metabolic syndrome parameters also improved following bariatric surgery, and whether weight-loss-independent metabolic changes affect airway processes and asthma pathobiology merits further research. Fulfilling knowledge gaps outlined in this review could facilitate the development of new therapeutic options for patients with obesity and asthma.

Dysregulated Metabolism in the Pathophysiology of Non-Allergic Obese Asthma.

Asthma is an obstructive airway disease that is characterized by reversible airway obstruction and is classically associated with atopic, TH2 driven inflammation. Landmark studies in the second half of the twentieth century identified eosinophils as a key mediator of inflammation and steroids, both inhaled and systemic, as a cornerstone of therapy. However, more recently other phenotypes of asthma have emerged that do not respond as well to traditional therapies. In particular, obese patients who develop asthma as adults are less likely to have eosinophilic airway inflammation and do not respond to traditional therapies. Obese patients often have metabolic comorbidities such as impaired glucose tolerance and dyslipidemias, also known as metabolic syndrome (MetS). The unified pathophysiology of metabolic syndrome is not known, however, several signaling pathways, such as the neuropeptide glucagon-like peptide-1 (GLP-1) and nitric oxide (NO) signaling have been shown to be dysregulated in MetS. These pathways are targeted by commercially available medications. This review discusses the potential roles that dysregulation of the GLP-1 and NO signaling pathways, along with arginine metabolism, play in the development of asthma in obese patients. GLP-1 receptors are found in high density in the lung and are also detectable in bronchoalveolar lavage fluid. NO has long been associated with asthma. We hypothesize that these derangements in metabolic signaling pathways underpin the asthmatic phenotype seen in obese patients with non-eosinophilic airway inflammation and poor response to established therapies. While still an active area of research, novel interventions are needed for this subset of patient who respond poorly to available asthma therapies.