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[This corrects the article DOI: 10.1371/journal.pone.0260706.].
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PURPOSE OF REVIEW: In this review, we discuss the current literature examining the impact air pollution and climate change has on asthma onset, control, and exacerbation. This review also addresses the risk of exposure to specific disproportionately affected communities, highlighting health disparities in exposure and asthma outcomes. RECENT FINDINGS: Recent studies have shifted from highlighting the associations between asthma exacerbations and indoor and outdoor air pollution. Studies are now focused on confirming the association of asthma incidence from these same exposures. Many studies have linked particulate matter to adverse asthma outcomes, however, the pollutant exposures that pose the greatest risk and the effect of natural disasters fueled by climate change are under current study. Some studies have observed that the true burden that pollutant exposures have on asthma outcomes occurs at the intersection of exposure and vulnerability. Future studies in this area will address social determinants of health, societal factors such as redlining and other systemic racism practices. SUMMARY: Although decades of research support the causal link between gaseous and particulate air pollution and the exacerbation of preexisting asthma, recent studies suggest air pollution can cause incident (new onset) asthma. Studies have started to focus on the underlying drivers of poor outcomes in asthma. Many of the structural impediments to high quality asthma care at the society level (e.g. poverty, redlining, systemic racism) also are risk factors for worsened climate events and air pollution exposure. The individuals in these disproportionately affected groups are doubly affected by worsened exposure and worsened access to care for the resultant asthma exacerbations or incident asthma. More research is needed to understand the specific climate and air pollution mitigation efforts where disproportionately affected communities would derive the most benefit.
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Contaminantes Atmosféricos , Contaminación del Aire , Asma , Humanos , Contaminantes Atmosféricos/efectos adversos , Cambio Climático , Justicia Ambiental , Determinantes Sociales de la Salud , Contaminación del Aire/efectos adversos , Asma/epidemiología , Asma/etiología , Material Particulado/efectos adversos , Exposición a Riesgos Ambientales/efectos adversosRESUMEN
This is an exciting time to be conducting asthma research. The recent development of targeted asthma biologics has validated the power of basic research to discover new molecules amenable to therapeutic intervention. Advances in high-throughput sequencing are providing a wealth of "omics" data about genetic and epigenetic underpinnings of asthma, as well as about new cellular interacting networks and potential endotypes in asthma. Airway epithelial cells have emerged not only as key sensors of the outside environment but also as central drivers of dysregulated mucosal immune responses in asthma. Emerging data suggest that the airway epithelium in asthma remembers prior encounters with environmental exposures, resulting in potentially long-lasting changes in structure and metabolism that render asthmatic individuals susceptible to subsequent exposures. Here we summarize recent insights into asthma biology, focusing on studies using human cells or tissue that were published in the past 2 years. The studies are organized thematically into 6 content areas to draw connections and spur future research (on genetics and epigenetics, prenatal and early-life origins, microbiome, immune and inflammatory pathways, asthma endotypes and biomarkers, and lung structural alterations). We highlight recent studies of airway epithelial dysfunction and response to viral infections and conclude with a framework for considering how bidirectional interactions between alterations in airway structure and mucosal immunity can lead to sustained lung dysfunction in asthma.
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Asma , Humanos , Asma/inmunología , Asma/genética , Animales , Microbiota/inmunología , Epigénesis Genética , Mucosa Respiratoria/inmunología , Biomarcadores , Inmunidad MucosaRESUMEN
It has been observed widely that, on average, Black individuals in the United States have lower FVC than White individuals, which is thought to reflect a combination of genetic, environmental, and socioeconomic factors that are difficult to disentangle. Debate therefore persists even after the American Thoracic Society's 2023 guidelines recommending race-neutral pulmonary function test (PFT) result interpretation strategies. Advocates of race-based PFT results interpretation argue that it allows for more precise measurement and will minimize disease misclassification. In contrast, recent studies have shown that low lung function in Black patients has clinical consequences. Furthermore, the use of race-based algorithms in medicine in general is increasingly being questioned for its risk of perpetuating structural health care disparities. Given these concerns, we believe it is time to adopt a race-neutral approach, but note that more research is urgently needed to understand how race-neutral approaches impact PFT results interpretation, clinical decision-making, and patient outcomes. In this brief case-based discussion, we offer a few examples of how a race-neutral PFT results interpretation strategy will impact individuals from racial and ethnic minority groups at different scenarios and stages of life.
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Etnicidad , Grupos Minoritarios , Pruebas de Función Respiratoria , Humanos , Fenómenos Fisiológicos Respiratorios , Estados Unidos , Negro o AfroamericanoRESUMEN
Protein kinase D (PKD) is a serine/threonine kinase family with three isoforms (PKD1-3) that are expressed in most cells and implicated in a wide array of signaling pathways, including cell growth, differentiation, transcription, secretion, polarization and actin turnover. Despite growing interest in PKD, relatively little is known about the role of PKD in immune responses. We recently published that inhibiting PKD limits proinflammatory cytokine secretion and leukocyte accumulation in mouse models of viral infection, and that PKD3 is highly expressed in the murine lung and immune cell populations. Here we focus on the immune-related phenotypes of PKD3 knockout mice. We report that PKD3 is necessary for maximal neutrophil accumulation in the lung following challenge with inhaled polyinosinic:polycytidylic acid, a double-stranded RNA, as well as following influenza A virus infection. Using reciprocal bone marrow chimeras, we found that PKD3 is required in the hematopoietic compartment for optimal neutrophil migration to the lung. Ex vivo transwell and chemokinesis assays confirmed that PKD3-/- neutrophils possess an intrinsic motility defect, partly because of reduced surface expression of CD18, which is critical for leukocyte migration. Finally, the peak of neutrophilia was significantly reduced in PKD3-/- mice after lethal influenza A virus infection. Together, these results demonstrate that PKD3 has an essential, and nonredundant, role in promoting neutrophil recruitment to the lung. A better understanding of the isoform-specific and cell type-specific activities of PKD has the potential to lead to novel therapeutics for respiratory illnesses.
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Neutrófilos , Proteína Quinasa C , Virosis , Animales , Ratones , Neutrófilos/metabolismo , Isoformas de Proteínas , Transducción de Señal , Proteína Quinasa C/metabolismoRESUMEN
Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.
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Asma/tratamiento farmacológico , Medicina de Precisión , Comités Consultivos , Asma/diagnóstico , Biomarcadores , Protocolos Clínicos , Ensayos Clínicos Fase II como Asunto , Humanos , Proyectos de Investigación , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos XRESUMEN
Airway epithelial barrier dysfunction is increasingly recognized as a key feature of asthma and other lung diseases. Respiratory viruses are responsible for a large fraction of asthma exacerbations, and are particularly potent at disrupting epithelial barrier function through pattern recognition receptor engagement leading to tight junction dysfunction. Although different mechanisms of barrier dysfunction have been described, relatively little is known about whether barrier integrity can be promoted to limit disease. Here, we tested three classes of drugs commonly prescribed to treat asthma for their ability to promote barrier function using a cell culture model of virus-induced airway epithelial barrier disruption. Specifically, we studied the corticosteroid budesonide, the long acting beta-agonist formoterol, and the leukotriene receptor antagonist montelukast for their ability to promote barrier integrity of a monolayer of human bronchial epithelial cells (16HBE) before exposure to the viral mimetic double-stranded RNA. Of the three, only budesonide treatment limited transepithelial electrical resistance and small molecule permeability (4 kDa FITC-dextran flux). Next, we used a mouse model of acute dsRNA challenge that induces transient epithelial barrier disruption in vivo, and studied the effects budesonide when administered prophylactically or therapeutically. We found that budesonide similarly protected against dsRNA-induced airway barrier disruption in the lung, independently of its effects on airway inflammation. Taken together, these data suggest that an under-appreciated effect of inhaled budesonide is to maintain or promote airway epithelial barrier integrity during respiratory viral infections.
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Asma/tratamiento farmacológico , Bronquios/efectos de los fármacos , Broncodilatadores/farmacología , Budesonida/farmacología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Poli I-C/antagonistas & inhibidores , Acetatos/farmacología , Administración por Inhalación , Animales , Asma/inducido químicamente , Asma/metabolismo , Asma/patología , Bronquios/metabolismo , Bronquios/patología , Línea Celular , Ciclopropanos/farmacología , Dextranos/metabolismo , Impedancia Eléctrica , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Fumarato de Formoterol/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Imitación Molecular , Poli I-C/farmacología , Quinolinas/farmacología , ARN Bicatenario/antagonistas & inhibidores , ARN Bicatenario/farmacología , ARN Viral/antagonistas & inhibidores , ARN Viral/farmacología , Sulfuros/farmacología , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismoRESUMEN
Asthma is an inflammatory disease of the airways characterized by intermittent episodes of wheezing, chest tightness, and cough. Many of the inflammatory pathways implicated in asthma involve cytokines and growth factors that activate Janus kinases (JAKs). The discovery of the JAK/signal transducer and activator of transcription (STAT) signaling pathway was a major breakthrough that revolutionized our understanding of cell growth and differentiation. JAK inhibitors are under active investigation for immune and inflammatory diseases, and they have demonstrated clinical efficacy in diseases such as rheumatoid arthritis and atopic dermatitis. Substantial preclinical data support the idea that inhibiting JAKs will ameliorate airway inflammation and hyperreactivity in asthma. Here, we review the rationale for use of JAK inhibitors in different asthma endotypes as well as the preclinical and early clinical evidence supporting such use. We review preclinical data from the use of systemic and inhaled JAK inhibitors in animal models of asthma and safety data based on the use of JAK inhibitors in other diseases. We conclude that JAK inhibitors have the potential to usher in a new era of anti-inflammatory treatment for asthma.
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Asma/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Animales , Vías de Administración de Medicamentos , Humanos , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/efectos adversos , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/inmunología , Factores de Transcripción STAT/inmunologíaRESUMEN
Combustion related particulate matter air pollution (PM) is associated with an increased risk of respiratory infections in adults. The exact mechanism underlying this association has not been determined. We hypothesized that increased concentrations of combustion related PM would result in dysregulation of the innate immune system. This epidemiological study includes 111 adult patients hospitalized with respiratory infections who underwent transcriptional analysis of their peripheral blood. We examined the association between gene expression at the time of hospitalization and ambient measurements of particulate air pollutants in the 28 days prior to hospitalization. For each pollutant and time lag, gene-specific linear models adjusting for infection type were fit using LIMMA (Linear Models For Microarray Data), and pathway/gene set analyses were performed using the CAMERA (Correlation Adjusted Mean Rank) program. Comparing patients with viral and/or bacterial infection, the expression patterns associated with air pollution exposure differed. Adjusting for the type of infection, increased concentrations of Delta-C (a marker of biomass smoke) and other PM were associated with upregulation of iron homeostasis and protein folding. Increased concentrations of black carbon (BC) were associated with upregulation of viral related gene pathways and downregulation of pathways related to antigen presentation. The pollutant/pathway associations differed by lag time and by type of infection. This study suggests that the effect of air pollution on the pathogenesis of respiratory infection may be pollutant, timing, and infection specific.
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Material Particulado/efectos adversos , Infecciones del Sistema Respiratorio/inmunología , Humo/efectos adversos , Transcriptoma , Adulto , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Inmunidad/genética , Masculino , New York/epidemiología , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/metabolismo , Hollín/efectos adversosRESUMEN
The airway epithelium represents a crucial line of defense against the spread of inhaled pathogens. As the epithelium is the first part of the body to be exposed to the inhaled environment, it must act as both a barrier to and sentinel against any inhaled agents. Despite its vital role in limiting the spread of inhaled pathogens, the airway epithelium is also regularly exposed to air pollutants which disrupt its normal function. Here we review the current understanding of the structure and composition of the airway epithelial barrier, as well as the impact of inhaled pollutants, including the reactive gas ozone and particulate matter, on epithelial function. We discuss the current in vitro, rodent model, and human exposure findings surrounding the impact of various inhaled pollutants on epithelial barrier function, mucus production, and mucociliary clearance. Detailed information on how inhaled pollutants impact epithelial structure and function will further our understanding of the adverse health effects of air pollution exposure.
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Contaminantes Atmosféricos/toxicidad , Ozono/toxicidad , Material Particulado/toxicidad , Mucosa Respiratoria/efectos de los fármacos , Pruebas de Toxicidad , AnimalesRESUMEN
The prevalence of unconventional oil and gas (UOG) operations raises concerns regarding the potential for adverse health outcomes following exposure to water tainted by mixtures of UOG associated chemicals. The potential effects that exposure to complex chemical mixtures has on the immune system have yet to be fully evaluated. In this study, effects on the immune system of adult mice exposed to a mixture of 23 chemicals that have been associated with water near active UOG operations were investigated. Female and male mice were exposed to the mixture via their drinking water for at least 8 weeks. At the end of the exposure, cellularity of primary and secondary immune organs, as well as an immune system function, were assessed using three different models of disease, i.e. house dust mite (HDM)-induced allergic airway disease, influenza A virus infection, and experimental autoimmune encephalomyelitis (EAE). The results indicated exposures resulted in different impacts on T-cell populations in each disease model. Furthermore, the consequences of exposure differed between female and male mice. Notably, exposure to the chemical mixture significantly increased EAE disease severity in females, but not in male, mice. These findings indicated that direct exposure to this mixture leads to multiple alterations in T-cell subsets and that these alterations differ between sexes. This suggested to us that direct exposure to UOG-associated chemicals may alter the adult immune system, leading to dysregulation in immune cellularity and function.
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Disruptores Endocrinos , Contaminantes Químicos del Agua , Animales , Mezclas Complejas , Femenino , Inmunidad , Masculino , RatonesRESUMEN
Lysophosphatidic acid (LPA) is a versatile lysolipid, and activates a variety of signaling cascades in many cell types. Extracellular LPA is produced from lysophosphatidylcholine (LPC) by the enzyme autotaxin (ATX), and binds to a family of G-protein coupled receptors on its target cells. Research by many groups continues to support the idea that LPA, and the ATX-LPA axis, have important roles in asthma and allergic airway inflammation. In vitro studies have shown that LPA activates many cell types implicated in airway inflammation, including eosinophils, mast cells, dendritic cells, lymphocytes, airway epithelial cells, and airway smooth muscle cells. In animal models ATX and LPA receptor antagonists have been shown to attenuate allergic airway inflammation and hyperreactivity, cardinal features of asthma in humans. ATX and LPA antagonists are currently under active development to treat lung fibrosis, cancer, and other conditions. If compounds with acceptable safety profiles can be identified, then it seems likely that they will be useful in inflammatory lung diseases like asthma.
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LisofosfolípidosRESUMEN
Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.
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Asma , Biomarcadores , Medicina de Precisión , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Proyectos de InvestigaciónRESUMEN
Exogenous electric fields are currently used in human therapy in a number of contexts. Interestingly, electric fields have also been shown to alter migration and function of immune cells, suggesting the potential for electric field-based immune therapy. Little is known as to the effect of electric field treatment (EFT) on the lung. To determine if EFT associates with changes in lung immune cell infiltration, we used a mouse model with varying methods of EFT application and measured cells and soluble mediators using flow cytometry and cytokine/chemokine multiplex. EFT was associated with a transient increase in lung neutrophils and decrease in eosinophils in naïve mice within 2 h of treatment, accompanied by an increase in IL-6 levels. In order to test whether EFT could alter eosinophil/neutrophil recruitment in a relevant disease model, a mouse model of allergic airway inflammation was used. Four EFT doses in allergen-sensitized mice resulted in increased neutrophil and reduced eosinophil infiltrates following allergen challenge, suggesting a durable change in inflammation by EFT. Mice with allergic inflammation were analyzed by flexiVent for measures of lung function. EFT-treated mice had increased inspiratory capacity and other measures of lung function were not diminished. These data suggest EFT may be used to manipulate immune cell infiltration in the lung without affecting lung function.