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Current American Thoracic Society (ATS) standards promote the use of race and ethnicity-specific reference equations for pulmonary function test (PFT) interpretation. There is rising concern that the use of race and ethnicity in PFT interpretation contributes to a false view of fixed differences between races and may mask the effects of differential exposures. This use of race and ethnicity may contribute to health disparities by norming differences in pulmonary function. In the United States and globally, race serves as a social construct that is based on appearance and reflects social values, structures, and practices. Classification of people into racial and ethnic groups differs geographically and temporally. These considerations challenge the notion that racial and ethnic categories have biological meaning and question the use of race in PFT interpretation. The ATS convened a diverse group of clinicians and investigators for a workshop in 2021 to evaluate the use of race and ethnicity in PFT interpretation. Review of evidence published since then that challenges current practice and continued discussion concluded with a recommendation to replace race and ethnicity-specific equations with race-neutral average reference equations, which must be accompanied with a broader re-evaluation of how PFTs are used to make clinical, employment, and insurance decisions. There was also a call to engage key stakeholders not represented in this workshop and a statement of caution regarding the uncertain effects and potential harms of this change. Other recommendations include continued research and education to understand the impact of the change, to improve the evidence for the use of PFTs in general, and to identify modifiable risk factors for reduced pulmonary function.
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Etnicidad , Sociedades , Humanos , Estados Unidos , Pruebas de Función RespiratoriaRESUMEN
The clinical definition of "difficult asthma" has expanded recently to include an ever-growing subset of patients with symptoms that cannot be controlled by conventional means, forcing the medical community to develop innovative therapeutics. Beneficial effects of coffee for subjects with asthma, primarily the effect of methylxanthine components, have long been described. Methylxanthines, including theophylline and caffeine, inhibit phosphodiesterases and downstream cAMP signaling to prevent mast cell degranulation while promoting immunomodulation (Peleman RA, Kips JC, Pauwels RA. Clin Exp Allergy 28: 53-56, 1998; Deshpande DA, Wang WCH, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JSK, Liggett SB. Nat Med 16: 1299-1304, 2010). Caffeine is also a bitter taste receptor agonist, binding to taste-sensing type 2 receptors (TAS2R) before releasing calcium to hyperpolarize airway smooth muscle membranes, inducing bronchodilation (Workman AD, Palmer JN, Adappa ND, Cohen NA. Curr Allergy Asthma Rep 15: 72, 2015; Devillier P, Naline E, Grassin-Delyle S. Pharmacol Ther 155: 11-21, 2015). Theophylline is conventionally used to treat asthma, whereas, according to the literature, the dosage required for orally administered caffeine has yielded modest improvement (Alfaro TM, Monteiro RA, Cunha RA, Cordeiro CR. Clin Respir J 12: 1283-1294, 2018). We sought to determine whether aerosolization of ultrafine caffeine particles (2.5-4 µm) directly to the lungs of susceptible A/J mice challenged with methacholine would improve pulmonary function via forced oscillation technique. In addition, we assessed whether nebulization of caffeine leads to changes in lung pathophysiology and bronchoalveolar lavage cell profiles. We found that mice that received aerosolized caffeine had statistically significant decreases in maximum airway resistance [6.3 vs. 3.9 cmH2O·s/mL at 62.5 mg/mL caffeine; confidence interval (CI) = -4.3, -0.4; P = 0.02] and significant delays in the time required to reach maximum resistance compared with that of controls (64.7 vs. 172.1 sec at 62.5 mg/mL caffeine, CI = 96.0, 118.9; P < 0.0001). Nebulized caffeine yielded a consistent effect on airway hyperresponsiveness at a range of doses without evidence of significant pathology relative to vehicle control.NEW & NOTEWORTHY For decades, coffee has been shown to improve symptoms in patients with asthma. One component, theophylline, is conventionally used to treat asthma, whereas the dosage required for orally administered caffeine has yielded modest improvement. We sought to determine whether aerosolization of caffeine directly to the lungs of susceptible A/J mice challenged with methacholine would alter pulmonary function via forced oscillation technique. We found nebulized caffeine yielded a consistent improvement on murine AHR.
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Rationale: There are no pharmacologic agents that modify emphysema progression in patients with chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of losartan, an angiotensin receptor blocker, to reduce emphysema progression. Methods: The trial was a multicenter, randomized, placebo-controlled trial conducted between May 2017 and January 2021. Eligible participants were aged ⩾40 years, had moderate to severe airflow obstruction, ⩾10 pack-years of smoking, mild-moderate emphysema on high-resolution computed tomography, and no medical indication for or intolerance of angiotensin receptor blockers. Treatment with losartan 100 mg daily or matching placebo (1:1) was randomly assigned. The primary outcome was emphysema progression on high-resolution computed tomography over 48 weeks. Secondary outcomes included the St George's Respiratory Questionnaire, the modified Medical Research Council dyspnea scale, the COPD Assessment Test, and the Physical Function-Short Form 20a. Measurements and Main Results: A total of 220 participants were enrolled; 58% were men, 19% were African American, and 24% were current smokers. The medians (interquartile ranges) for age were 65 (61-73) years and 48 (36-59) for percent predicted FEV1 after bronchodilator use. The mean (95% confidence interval) percentage emphysema progression was 1.35% (0.67-2.03) in the losartan group versus 0.66% (0.09-1.23) in the placebo group (P = NS). Conclusions: Losartan did not prevent emphysema progression in people with COPD with mild-moderate emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT02696564).
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Enfisema , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Anciano , Antagonistas de Receptores de Angiotensina/uso terapéutico , Broncodilatadores/uso terapéutico , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado , Humanos , Losartán/uso terapéutico , Masculino , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfisema Pulmonar/complicaciones , Enfisema Pulmonar/tratamiento farmacológicoRESUMEN
Aortic dissection and rupture are the major causes of premature death in persons with Marfan syndrome (MFS), a rare genetic disorder featuring cardiovascular, skeletal, and ocular impairments. We and others have found that obstructive sleep apnea (OSA) confers significant vascular stress in this population and may accelerate aortic disease progression. We hypothesized that D-dimer, a diagnostic biomarker for several types of vascular injury that is also elevated in persons with MFS with aortic enlargement, may be sensitive to cardiovascular stresses caused by OSA. To test this concept, we recruited 16 persons with MFS without aortic dissection and randomized them to two nights of polysomnography, without (baseline) and with OSA treatment: continuous positive airway pressure (CPAP). In addition to scoring OSA by the apnea-hypopnea index (AHI), beat-by-beat systolic BP (SBP) and pulse-pressure (PP) fluctuations were quantified. Morning blood samples were also assayed for D-dimer levels. In this cohort (male:female, 10:6; age, 36 ± 13 yr; aortic diameter, 4 ± 1 cm), CPAP eliminated OSA (AHI: 20 ± 17 vs. 3 ± 2 events/h, P = 0.001) and decreased fluctuations in SBP (13 ± 4 vs. 9 ± 3 mmHg, P = 0.011) and PP (7 ± 2 vs. 5 ± 2 mmHg, P = 0.013). CPAP also reduced D-dimer levels from 1,108 ± 656 to 882 ± 532 ng/mL (P = 0.023). Linear regression revealed a positive association between the maximum PP during OSA and D-dimer in both the unadjusted (r = 0.523, P = 0.038) and a model adjusted for contemporaneous aortic root diameter (r = 0.733, P = 0.028). Our study revealed that overnight CPAP reduces D-dimer levels commensurate with the elimination of OSA and concomitant hemodynamic fluctuations. Morning D-dimer measurements together with OSA screening might serve as predictors of vascular injury in MFS.NEW & NOTEWORTHY What is New? Surges in blood pressure caused by obstructive sleep apnea during sleep increase vascular stress and D-dimer levels in Marfan syndrome. Elevations in D-dimer can be lowered with CPAP. What is Noteworthy? D-dimer levels might serve as a marker for determining the significance of obstructive sleep apnea in persons with Marfan syndrome. D-dimer or obstructive sleep apnea screening is a potential method to identify persons with Marfan syndrome at risk for adverse cardiovascular events.
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Síndrome de Marfan , Apnea Obstructiva del Sueño , Adulto , Presión Sanguínea/fisiología , Presión de las Vías Aéreas Positiva Contínua , Femenino , Productos de Degradación de Fibrina-Fibrinógeno , Humanos , Masculino , Síndrome de Marfan/complicaciones , Síndrome de Marfan/diagnóstico , Persona de Mediana Edad , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/terapia , Adulto JovenRESUMEN
The coronavirus disease (COVID-19) pandemic is sweeping the globe. Even with a number of effective vaccines being approved and available to the public, new cases and escalating mortality are climbing every day. ACE2 (angiotensin-converting enzyme 2) is the primary receptor for the COVID-19 causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its complexation with spike proteins plays a crucial role in viral entry into host cells and the subsequent infection. Blocking this binding event or reducing the accessibility of the virus to the ACE2 receptor, represents an alternative strategy to prevent COVID-19. In addition, the biological significance of ACE2 in modulating the innate immune system and tissue repair cascades and anchors its therapeutic potential for treating the infected patients. In this viewpoint article, we review the current efforts of exploiting ACE2 as a therapeutic target to address this dire medical need. We also provide a holistic view of the pros and cons of each treatment strategy. We highlight the fundamental and translational challenges in moving these research endeavors to clinical applications.
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Enzima Convertidora de Angiotensina 2/inmunología , Tratamiento Farmacológico de COVID-19 , Sistemas de Liberación de Medicamentos , Inmunidad Innata/efectos de los fármacos , SARS-CoV-2/inmunología , COVID-19/inmunología , Humanos , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
Background: Current tobacco treatment guidelines have established the efficacy of available interventions, but they do not provide detailed guidance for common implementation questions frequently faced in the clinic. An evidence-based guideline was created that addresses several pharmacotherapy-initiation questions that routinely confront treatment teams.Methods: Individuals with diverse expertise related to smoking cessation were empaneled to prioritize questions and outcomes important to clinicians. An evidence-synthesis team conducted systematic reviews, which informed recommendations to answer the questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in the estimated effects and the strength of recommendations.Results: The guideline panel formulated five strong recommendations and two conditional recommendations regarding pharmacotherapy choices. Strong recommendations include using varenicline rather than a nicotine patch, using varenicline rather than bupropion, using varenicline rather than a nicotine patch in adults with a comorbid psychiatric condition, initiating varenicline in adults even if they are unready to quit, and using controller therapy for an extended treatment duration greater than 12 weeks. Conditional recommendations include combining a nicotine patch with varenicline rather than using varenicline alone and using varenicline rather than electronic cigarettes.Conclusions: Seven recommendations are provided, which represent simple practice changes that are likely to increase the effectiveness of tobacco-dependence pharmacotherapy.
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Bupropión/normas , Guías de Práctica Clínica como Asunto , Agentes para el Cese del Hábito de Fumar/normas , Tabaquismo/tratamiento farmacológico , Vareniclina/normas , Adulto , Anciano , Anciano de 80 o más Años , Bupropión/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Estados Unidos , Vareniclina/uso terapéuticoRESUMEN
Perturbations in airway mucus properties contribute to lung function decline in patients with chronic obstructive pulmonary disease (COPD). While alterations in bulk mucus rheology have been widely explored, microscopic mucus properties that directly impact on the dynamics of microorganisms and immune cells in the COPD lungs are yet to be investigated.We hypothesised that a tightened mesh structure of spontaneously expectorated mucus (i.e. sputum) would contribute to increased COPD disease severity. Here, we investigated whether the mesh size of COPD sputum, quantified by muco-inert nanoparticle (MIP) diffusion, correlated with sputum composition and lung function measurements.The microstructure of COPD sputum was assessed based on the mean squared displacement (MSD) of variously sized MIPs measured by multiple particle tracking. MSD values were correlated with sputum composition and spirometry. In total, 33 samples collected from COPD or non-COPD individuals were analysed.We found that 100â nm MIPs differentiated microstructural features of COPD sputum. The mobility of MIPs was more hindered in sputum samples from patients with severe COPD, suggesting a tighter mucus mesh size. Specifically, MSD values inversely correlated with lung function.These findings suggest that sputum microstructure may serve as a novel risk factor for COPD progression and severity.
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Nanopartículas/química , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Fumar/efectos adversos , Esputo , Difusión , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Reología , Factores de Riesgo , EspirometríaRESUMEN
Vascular Ehlers-Danlos syndrome (vEDS) is a connective tissue disorder due to defective type III collagen production and is associated with arterial rupture, spontaneous intestinal perforation, and gravid uterine rupture. Spontaneous pneumothorax and/or hemothorax (P/HTX) also occurs in vEDS patients. The temporal relation of pulmonary manifestations to arterial and intestinal complications in vEDS has not been well described. This was investigated in a multi-institutional retrospective case series of vEDS patients with confirmatory testing for COL3A1 mutation between 2000 and 2012. Data abstracted included demographics, family histories, presentation, and management of associated complications. Ninety-six cases (39% males, mean age 38.6 ± 15.5 years, range 8-79) had confirmatory testing for vEDS. P/HTX was documented in 17 (17.7%) cases. Most P/HTX preceded the diagnosis of vEDS (81%). Diagnosis of vEDS was made after arterial or intestinal complications at a mean of 7 years (range 0-26) post the initial P/HTX. In conclusion, spontaneous P/HTX is an early manifestation of vEDS frequently preceding an arterial complication or intestinal perforation. Thus, a spontaneous P/HTX in a young patient should trigger a differential diagnosis that includes vEDS. This should lead to an investigation of other vEDS features and subsequent genetic testing if vEDS features are present.
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Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/genética , Hemotórax/etiología , Fenotipo , Neumotórax/etiología , Adolescente , Adulto , Anciano , Niño , Preescolar , Colágeno Tipo III/genética , Estudios Transversales , Síndrome de Ehlers-Danlos/diagnóstico , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Hemotórax/diagnóstico , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neumotórax/diagnóstico , Prevalencia , Adulto JovenRESUMEN
RATIONALE: The tobacco harm reduction literature is replete with vague language, far-reaching claims, and unwarranted certainty. The American Thoracic Society has increasingly recognized the need for a framework for reliably making such claims. Evidence-based standards improving the scientific value and transparency of harm reduction claims are expected to improve their trustworthiness, clarity, and consistency. METHODS: Experts from relevant American Thoracic Society committees identified key topic areas for discussion. Literature search strategy included English language articles across Medline, Google Scholar, and the Cochrane Collaborative databases, with expanded search terms including tobacco, addiction, smoking, cigarettes, nicotine, and harm reduction. Workgroup members synthesized their evidentiary summaries into a list of candidate topics suitable for inclusion in the final report. Breakout groups developed detailed content maps of each topic area, including points to be considered for suggested recommendations. Successive draft recommendations were modified using an iterative consensus process until unanimous approval was achieved. Patient representatives ensured the document's relevance to the lay public. RESULTS: Fifteen recommendations were identified, organized into four framework elements dealing with: estimating harm reduction among individuals, making claims on the basis of population impact, appropriately careful use of language, and ethical considerations in harm reduction. DISCUSSION: This statement clarifies important principles guiding valid direct and inferential harm reduction claims. Ideals for effective communication with the lay public and attention to unique ethical concerns are also delineated. The authors call for formal systems of grading harm reduction evidence and regulatory assurances of longitudinal surveillance systems to document the impact of harm reduction policies.
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Reducción del Daño , Comunicación en Salud , Política de Salud , Nicotiana/efectos adversos , Fumar/efectos adversos , Humanos , Sociedades Médicas , Estados UnidosRESUMEN
Children and adolescents are highly susceptible to nicotine addiction, which affects their brain development, even in those who smoke infrequently. Young people who become addicted to nicotine are at greater risk of becoming lifelong tobacco consumers. The use of nicotine-delivering electronic cigarettes has risen dramatically among youths worldwide. In addition to physical dependence, adolescents are susceptible to social and environmental influences to use electronic cigarettes. The product design, flavours, marketing, and perception of safety and acceptability have increased the appeal of electronic cigarettes to young people, thus leading to new generations addicted to nicotine. Moreover, there is growing evidence that electronic cigarettes in children and adolescents serve as a gateway to cigarette smoking. There can be no argument for harm reduction in children. To protect this vulnerable population from electronic cigarettes and other nicotine delivery devices, we recommend that electronic cigarettes be regulated as tobacco products and included in smoke-free policies. Sale of electronic cigarettes should be barred to youths worldwide. Flavouring should be prohibited in electronic cigarettes, and advertising accessible by youths and young adults be banned. Finally, we recommend greater research on the health effects of electronic cigarettes and surveillance of use across different countries.
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Fumar Cigarrillos/epidemiología , Sistemas Electrónicos de Liberación de Nicotina/economía , Vapeo/efectos adversos , Vapeo/legislación & jurisprudencia , Adolescente , Publicidad/legislación & jurisprudencia , Niño , Congresos como Asunto , Salud Global , Reducción del Daño , Humanos , Sociedades Médicas , Vapeo/epidemiología , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The Centers for Medicare and Medicaid Services' requirement to integrate tobacco treatment with lung cancer screening (LCS) has served as a catalyst for motivating pulmonary medicine clinicians to improve upon their ability to effectively treat tobacco dependence. To do so, clinicians need to be well versed in the behavioral and pharmacologic tools that promote smoking cessation. RECENT FINDINGS: The current review outlines current strategies for treating tobacco dependence, focusing on the important interplay between counseling and pharmacotherapy. Studies that have been found to be particularly effective in patients with smoking-related lung disease and in the LCS setting are reviewed. New therapies that are in the pipeline, as well as novel strategies aimed at improving both adoption and effectiveness of existing therapies, are discussed. SUMMARY: Treating tobacco dependence improves mortality and quality of life far more than the limited therapies available to treat smoking-related lung disease. Novel strategies to making tobacco treatment services more widely available, particularly to vulnerable patient populations, are needed to further decrease smoking-related morbidity and mortality. The Affordable Care Act's greater focus on prevention represents a moment of opportunity for healthcare providers and systems to engage in these efforts.
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Consejo Dirigido , Neoplasias Pulmonares/diagnóstico , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Cese del Hábito de Fumar , Tabaquismo/terapia , Bupropión/uso terapéutico , Detección Precoz del Cáncer , Humanos , Dispositivos para Dejar de Fumar Tabaco , Vareniclina/uso terapéuticoRESUMEN
INTRODUCTION: Since the mid-20th century, the scientific community has substantially improved its understanding of the worldwide tobacco epidemic. Although significant progress has been made, the sheer enormity and scope of the global problem put it on track to take a billion lives this century. Curbing the epidemic will require maximizing the impact of proven tools as well as the development of new, breakthrough methods to help interrupt the spread of nicotine addiction and reduce the downstream morbidity. METHODS: Members of the Tobacco Action Committee of the American Thoracic Society queried bibliographic databases, including Medline, Embase, and the Cochrane Collaborative, to identify primary sources and reviews relevant to the epidemic. Exploded search terms were used to identify evidence, including tobacco, addiction, smoking, cigarettes, nicotine, and smoking cessation. Evidence was consolidated into three thematic areas: (1) determinants of risk, (2) maternal-fetal exposure, and (3) current tobacco users. Expert panel consensus regarding current gaps in understanding and recommendations for future research priorities was generated through iterative discussion. RESULTS: Although much has been accomplished, significant gaps in understanding remain. Implementation often lags well behind insight. This report identifies a number of investigative opportunities for significantly reducing the toll of tobacco use, including: (1) the need for novel, nonlinear models of population-based disease control; (2) refinement of "real-world" models of clinical intervention in trial design; and (3) understanding of mechanisms by which intrauterine smoke exposure may lead to persistent, tobacco-related chronic disease. DISCUSSION: In the coming era of tobacco research, pooled talent from multiple disciplines will be required to further illuminate the complex social, environmental and biological codeterminants of tobacco dependence.
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Investigación Biomédica/organización & administración , Investigación Biomédica/tendencias , Cese del Hábito de Fumar , Tabaquismo/epidemiología , Tabaquismo/terapia , Femenino , Predicción , Humanos , Masculino , Intercambio Materno-Fetal , Embarazo , Sociedades Médicas , Tabaquismo/prevención & control , Estados Unidos/epidemiologíaRESUMEN
The alveolar compartment, the fundamental gas exchange unit in the lung, is critical for tissue oxygenation and viability. We explored hepatocyte growth factor (HGF), a pleiotrophic cytokine that promotes epithelial proliferation, morphogenesis, migration, and resistance to apoptosis, as a candidate mediator of alveolar formation and regeneration. Mice deficient in the expression of the HGF receptor Met in lung epithelial cells demonstrated impaired airspace formation marked by a reduction in alveolar epithelial cell abundance and survival, truncation of the pulmonary vascular bed, and enhanced oxidative stress. Administration of recombinant HGF to tight-skin mice, an established genetic emphysema model, attenuated airspace enlargement and reduced oxidative stress. Repair in the TSK/+ mouse was punctuated by enhanced akt and stat3 activation. HGF treatment of an alveolar epithelial cell line not only induced proliferation and scattering of the cells but also conferred protection against staurosporine-induced apoptosis, properties critical for alveolar septation. HGF promoted cell survival was attenuated by akt inhibition. Primary alveolar epithelial cells treated with HGF showed improved survival and enhanced antioxidant production. In conclusion, using both loss-of-function and gain-of-function maneuvers, we show that HGF signaling is necessary for alveolar homeostasis in the developing lung and that augmentation of HGF signaling can improve airspace morphology in murine emphysema. Our studies converge on prosurvival signaling and antioxidant protection as critical pathways in HGF-mediated airspace maintenance or repair. These findings support the exploration of HGF signaling enhancement for diseases of the airspace.
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Factor de Crecimiento de Hepatocito , Homeostasis , Proteínas Proto-Oncogénicas c-met , Alveolos Pulmonares , Animales , Movimiento Celular/genética , Proliferación Celular , Células Epiteliales/citología , Células Epiteliales/metabolismo , Factor de Crecimiento de Hepatocito/administración & dosificación , Factor de Crecimiento de Hepatocito/genética , Factor de Crecimiento de Hepatocito/metabolismo , Ratones , Morfogénesis/genética , Morfogénesis/fisiología , Proteínas Proto-Oncogénicas c-met/deficiencia , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/fisiología , Enfisema Pulmonar/genética , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/fisiopatología , Transducción de Señal , Supervivencia Tisular/genéticaAsunto(s)
Efectos Tardíos de la Exposición Prenatal , Productos de Tabaco , Vapeo , Aerosoles , Animales , Electrónica , Femenino , Pulmón , Ratones , Desarrollo de Músculos , Embarazo , Vapeo/efectos adversosRESUMEN
Neonates and infants have a higher morbidity and mortality associated with lower respiratory tract illnesses compared with older children. To identify age-related and longitudinal differences in the cellular immune response to acute lung injury (ALI), neonatal and juvenile mice were given Escherichia coli LPS using a novel, minimally invasive aspiration technique. Neonatal and juvenile mice received between 3.75 and 7.5 mg/kg LPS by intrapharyngeal aspiration. Airway and lung cells were isolated and characterized by flow cytometry, cytokine/chemokine mRNA expression from lung homogenates was quantified, and lung morphometry and injury scores were performed. LPS-treated neonatal mice underwent adoptive transfer with adult T regulatory cells (Tregs). After LPS aspiration, lung monocytes isolated from neonatal mice had a predominant M2 phenotype, whereas lung monocytes from juvenile mice displayed a mixed M1/M2 phenotype. At 72 hours after LPS exposure, neonatal lungs were slower to resolve inflammation and expressed lower mRNA levels of CCL2, CCL5, CXCL10, and IL-10. Juvenile, but not neonatal, mice demonstrated a significant increase in airway Tregs after LPS exposure. Adoptive transfer of adult Tregs into LPS-challenged neonatal mice resulted in reduced lung inflammation and improved weight gain. These findings underscore several vulnerabilities in the neonatal immune response to LPS-induced ALI. Most striking was the deficiency in airway Tregs after LPS aspiration. Adoptive transfer of adult Tregs mitigated LPS-induced ALI in neonatal mice, highlighting the importance of age-related differences in Tregs and their response to ALI during early postnatal development.
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Lesión Pulmonar Aguda/inmunología , Animales Recién Nacidos/inmunología , Lipopolisacáridos/inmunología , Pulmón/inmunología , Traslado Adoptivo/métodos , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocina CCL2/inmunología , Quimiocina CCL5/inmunología , Quimiocina CXCL10/inmunología , Modelos Animales de Enfermedad , Femenino , Inflamación/inmunología , Interleucina-10/inmunología , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Embarazo , Linfocitos T Reguladores/inmunologíaRESUMEN
Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P < 9.57 × 10(-8)). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 × 10(-8) < P ≤ 4.6 × 10(-6)). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 × 10(-9)) and MYH15 (P = 1.62 × 10(-6)), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.
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Enfermedad Pulmonar Obstructiva Crónica/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Sitios de Carácter Cuantitativo , Riesgo , Sarcoglicanos/genética , Sarcoglicanos/metabolismoRESUMEN
We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.
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Segregación Cromosómica/genética , ARN Polimerasas Dirigidas por ADN/genética , Exoma/genética , Padre , Síndrome de Klippel-Feil/genética , Disostosis Mandibulofacial/genética , Mutación/genética , Núcleo Familiar , Niño , Biología Computacional , Análisis Mutacional de ADN , Familia , Femenino , Estudios de Asociación Genética , Humanos , Recién Nacido , Síndrome de Klippel-Feil/complicaciones , Masculino , Disostosis Mandibulofacial/complicaciones , LinajeRESUMEN
Bronchopulmonary dysplasia (BPD), a common chronic respiratory disease that occurs after premature birth, is believed to be secondary to oxidative damage from hyperoxia and inflammation, which leads to impaired alveolar formation and chronic lung dysfunction. We hypothesized that extracellular superoxide dismutase (SOD)3, an antioxidant uniquely targeted to the extracellular matrix (ECM) and alveolar fluid, might have a different response (down-regulation) to hyperoxic injury and recovery in room air (RA), thereby contributing to the persistent airspace injury and inflammation. We used a murine BPD model using postnatal hyperoxia (O2) (4 or 5 d) followed by short-term recovery (14 d) in RA, which mimics the durable effects after injury during alveolar development. This was associated with significantly increased mRNA expression for antioxidant genes mediated by nuclear factor erythroid 2-related factor (Nrf2) in the O2 (n = 4) versus RA group (n = 5). SOD3, an Nrf2-independent antioxidant, was significantly reduced in the O2-exposed mice compared with RA. Immunohistochemistry revealed decreased and disrupted SOD3 deposition in the alveolar ECM of O2-exposed mice. Furthermore, this distinct hyperoxic antioxidant and injury profile was reproducible in murine lung epithelial 12 cells exposed to O2. Overexpression of SOD3 rescued the injury measures in the O2-exposed cells. We establish that reduced SOD3 expression correlates with alveolar injury measures in the recovered neonatal hyperoxic lung, and SOD3 overexpression attenuates hyperoxic injury in an alveolar epithelial cell line. Such findings suggest a candidate mechanism for the pathogenesis of BPD that may lead to targeted interventions.