Sharmilee M. Nyenhuis

Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation

RATIONALE Bioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis. OBJECTIVES To define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation. METHODS We investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway-specific genetically modified mice. MEASUREMENTS AND MAIN RESULTS Subsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22:5 and 22:6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation. CONCLUSIONS The ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy.

Recruited Alveolar Macrophages, in Response to Airway Epithelial–Derived Monocyte Chemoattractant Protein 1/CCL2, Regulate Airway Inflammation and Remodeling in Allergic Asthma

Although alveolar macrophages (AMs) from patients with asthma are known to be functionally different from those of healthy individuals, the mechanism by which this transformation occurs has not been fully elucidated in asthma. The goal of this study was to define the mechanisms that control AM phenotypic and functional transformation in response to acute allergic airway inflammation. The phenotype and functional characteristics of AMs obtained from human subjects with asthma after subsegmental bronchoprovocation with allergen was studied. Using macrophage-depleted mice, the role and trafficking of AM populations was determined using an acute allergic lung inflammation model. We observed that depletion of AMs in a mouse allergic asthma model attenuates Th2-type allergic lung inflammation and its consequent airway remodeling. In both human and mouse, endobronchial challenge with allergen induced a marked increase in monocyte chemotactic proteins (MCPs) in bronchoalveolar fluid, concomitant with the rapid appearance of a monocyte-derived population of AMs. Furthermore, airway allergen challenge of allergic subjects with mild asthma skewed the pattern of AM gene expression toward high levels of the receptor for MCP1 (CCR2/MCP1R) and expression of M2 phenotypic proteins, whereas most proinflammatory genes were highly suppressed. CCL2/MCP-1 gene expression was prominent in bronchial epithelial cells in a mouse allergic asthma model, and in vitro studies indicate that bronchial epithelial cells produced abundant MCP-1 in response to house dust mite allergen. Thus, our study indicates that bronchial allergen challenge induces the recruitment of blood monocytes along a chemotactic gradient generated by allergen-exposed bronchial epithelial cells.

Interventions to Reduce Rehospitalizations after Chronic Obstructive Pulmonary Disease Exacerbations. A Systematic Review

RATIONALE Approximately 20% of patients hospitalized for COPD exacerbations in the United States will be readmitted within 30 days. The Centers for Medicare and Medicaid Services has recently proposed to revise the Hospital Readmissions Reduction Program to financially penalize hospitals with high all-cause 30-day rehospitalization rates after a hospitalization for COPD exacerbation on or after October 1, 2014. OBJECTIVES To report the results of a systematic review of randomized clinical trials evaluating interventions to reduce the rehospitalizations after COPD exacerbations. METHODS Multiple electronic databases were systematically searched to identify relevant studies published between January 1966 and June 2013. Titles, abstracts, and, subsequently, full-text articles were assessed for eligibility. Each study was appraised using predefined criteria. MEASUREMENTS AND MAIN RESULTS Among 913 titles and abstracts screened, 5 studies (1,393 participants) met eligibility criteria. All studies had a primary outcome of rehospitalization at 6 or 12 months. No study examined 30-day rehospitalization as the primary outcome. Each study tested a different set of interventions. Two studies (one conducted in Canada and one conducted in Spain and Belgium) showed a decrease in all-cause rehospitalization over 12 months in the intervention group versus comparator group (mean number of hospitalizations per patient, 1.0 vs. 1.8; P = 0.01; percent hospitalized, 45 vs. 67%; P = 0.028; respectively). The only study conducted in the United States found a greater than twofold higher risk of mortality in the intervention group (17 vs. 7%, P = 0.003) but no significant difference in rehospitalizations. It was unclear which set of interventions was effective or harmful. CONCLUSIONS The evidence base is inadequate to recommend specific interventions to reduce rehospitalizations in this population and does not justify penalizing hospitals for high 30-day rehospitalization rates after COPD exacerbations.

Rhinitis in the elderly.

By 2050, the US aging population will nearly double. It will be increasingly important for health care providers to diagnose and manage rhinitis. Nasal symptoms of rhinorrhea, congestion, sneezing, nasal/ocular pruritus, and postnasal drainage affect up to 32% of older adults, and can impact quality of life. Several underlying factors associated with aging may contribute to the pathogenesis of rhinitis in older adults. Although treatment options for rhinitis exist, special considerations need to be made because comorbidities, limited income, memory loss, and side effects of medications are common in older adults and may impact outcomes.

Airway neutrophil inflammatory phenotype in older subjects with asthma

Asthma in the elderly has been inadequately studied. The age demographic >65 years old is the fastest growing in the United States, and asthma in the elderly population is frequently underdiagnosed and undertreated(1). Furthermore, elderly asthmatics also have a higher rate of severe exacerbations, emergency department visits, and hospitalizations than younger asthmatics which represents significant disease impairment and risk(2). The airway inflammation in older asthma subjects differs from younger patients, which suggests that the phenotype of asthma in older asthmatics may be different. An understanding of this phenotype of asthma will be important for the diagnosis of the disease, determining optimal therapies, and improvement in the morbidity and mortality in the growing elderly asthmatic population.

Obstructive sleep apnea and asthma: Associations and treatment implications

Obstructive sleep apnea (OSA) and asthma are highly prevalent respiratory disorders and are frequently co-morbid. Risk factors common to the two diseases include obesity, rhinitis, and gastroesophageal reflux (GER). Observational and experimental evidence implicates airways and systemic inflammation, neuromechanical effects of recurrent upper airway collapse, and asthma-controlling medications (corticosteroids) as additional explanatory factors. Therefore, undiagnosed or inadequately treated OSA may adversely affect control of asthma and vice versa. It is important for clinicians to be vigilant and specifically address weight-control, nasal obstruction, and GER in these populations. Utilizing validated screening instruments to affirm high risk of co-morbid OSA or asthma in persistently symptomatic patients will allow clinicians to cost-effectively test and treat appropriate patients, potentially improving outcomes. While non-invasive ventilation in acute asthma improves outcomes, the role of chronic continuous positive airway pressure (CPAP; the first-line treatment for OSA) in improving long-term asthma control is not known. Future research should focus on the impact of optimal CPAP therapy and adherence on asthma symptoms and outcomes.

Characterization of leukotrienes in a pilot study of older asthma subjects

Leukotrienes are pro-inflammatory lipid mediators, which are important in asthma leading to its characteristic features of airway bronchoconstriction, wheezing, increased mucus secretion and decreased mucociliary clearance. Aging results in changes in immune function and we have previously demonstrated age-related differences in levels of neutrophil elastase, MMP-9, and IL-8 in asthma subjects. We sought to determine whether leukotriene levels differed between young and older asthmatics.

Rhinitis in Older Adults

Rhinitis symptoms of rhinorrhea, congestion, sneezing, nasal/ocular pruritis, and postnasal drainage can significantly affect the quality of life for older adults. As the US population ages, it will be increasingly important for health-care providers to effectively diagnose and manage rhinitis. Rhinitis is categorized broadly into allergic rhinitis and non-allergic rhinitis. Environmental changes and avoidance measures are a primary means of intervention. In addition, there are several topical therapies (nasal sprays) that can be effective for symptom control.

Polyunsaturated lysophosphatidic acid as a potential asthma biomarker

Lysophosphatidic acid (LPA), a lipid mediator in biological fluids and tissues, is generated mainly by autotaxin that hydrolyzes lysophosphatidylcholine to LPA and choline. Total LPA levels are increased in bronchoalveolar lavage fluid from asthmatic lung, and are strongly induced following subsegmental bronchoprovocation with allergen in subjects with allergic asthma. Polyunsaturated molecular species of LPA (C22:5 and C22:6) are selectively synthesized in the airways of asthma subjects following allergen challenge and in mouse models of allergic airway inflammation, having been identified and quantified by LC/MS/MS lipidomics. This review discusses current knowledge of LPA production in asthmatic lung and the potential utility of polyunsaturated LPA molecular species as novel biomarkers in bronchoalveolar lavage fluid and exhaled breath condensate of asthma subjects.

Engaging stakeholders to design a comparative effectiveness trial in children with uncontrolled asthma

AIM To present the methods and outcomes of stakeholder engagement in the development of interventions for children presenting to the emergency department (ED) for uncontrolled asthma. METHODS We engaged stakeholders (caregivers, physicians, nurses, administrators) from six EDs in a three-phase process to: define design requirements; prototype and refine; and evaluate. RESULTS Interviews among 28 stakeholders yielded themes regarding in-home asthma management practices and ED discharge experiences. Quantitative and qualitative evaluation showed strong preference for the new discharge tool over current tools. CONCLUSION Engaging end-users in contextual inquiry resulted in CAPE (CHICAGO Action Plan after ED discharge), a new stakeholder-balanced discharge tool, which is being tested in a multicenter comparative effectiveness trial.