Showing papers by "National Jewish Health published in 2009"

The Roles of Antimicrobial Peptides in Innate Host Defense

Abstract: Antimicrobial peptides (AMPs) are multi-functional peptides whose fundamental biological role in vivo has been proposed to be the elimination of pathogenic microorganisms, including Gram-positive and -negative bacteria, fungi, and viruses. Genes encoding these peptides are expressed in a variety of cells in the host, including circulating phagocytic cells and mucosal epithelial cells, demonstrating a wide range of utility in the innate immune system. Expression of these genes is tightly regulated; they are induced by pathogens and cytokines as part of the host defense response, and they can be suppressed by bacterial virulence factors and environmental factors which can lead to increased susceptibility to infection. New research has also cast light on alternative functionalities, including immunomodulatory activities, which are related to their unique structural characteristics. These peptides represent not only an important component of innate host defense against microbial colonization and a link between innate and adaptive immunity, but also form a foundation for the development of new therapeutic agents.

Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury.

Abstract: The primary function of neutrophils in host defense is to contain and eradicate invading microbial pathogens. This is achieved through a series of swift and highly coordinated responses culminating in ingestion (phagocytosis) and killing of invading microbes. While these tasks are usually performed without injury to host tissues, in pathologic circumstances such as sepsis, potent antimicrobial compounds can be released extracellularly, inducing a spectrum of responses in host cells ranging from activation to injury and death. In the lung, such inflammatory damage is believed to contribute to the pathogenesis of diverse lung diseases, including acute lung injury and the acute respiratory distress syndrome, chronic obstructive lung disease, and cystic fibrosis. In these disorders, epithelial cells are targets of leukocyte-derived antimicrobial products, including proteinases and oxidants. Herein, we review the mechanisms involved in the physiologic process of neutrophil transepithelial migration, including the role of specific adhesion molecules on the leukocyte and epithelial cells. We examine the responses of the epithelial cells to the itinerant leukocytes and their cytotoxic products and the consequences of this for lung injury and repair. This paradigm has important clinical implications because of the potential for selective blockade of these pathways to prevent or attenuate lung injury.

Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA

Abstract: The purpose of this study was to identify rheumatoid arthritis (RA)-related autoantibodies in subjects with interstitial lung disease (ILD) and no articular findings of RA, supporting the hypothesis that RA-related autoimmunity may be generated in non-articular sites, such as the lung. This was a retrospective chart review utilizing clinic databases of patients with ILD to identify cases with lung disease, RA-related autoantibody positivity, and no clinical evidence of articular RA. Four patients with ILD, RF, and anti-CCP positivity and no articular findings of RA were identified. All four patients were male with a mean age at time of diagnosis of ILD of 70 years old. All had a history of smoking. Three patients died within 2 years of diagnosis of ILD and never developed articular symptoms consistent with RA; the final case met full criteria for articular RA several months after stopping immunosuppressive treatment for ILD. RF and anti-CCP can be present in smokers with ILD without clinical evidence of articular RA and in one case symptomatic ILD and autoantibody positivity preceded the development of articular RA. These findings suggest that RA-specific autoimmunity may be generated due to immunologic interactions in the lung and may be related to environmental factors such as smoking.

Brain activation changes before and after PAP treatment in obstructive sleep apnea.

Abstract: study objectives : Obstructive sleep apnea syndrome (OSAS) is asso- ciated with cognitive and functional deficits, most of which are corrected after positive airway pressure (PAP) treatment. Previous studies inves- tigating the neural underpinnings of OSAS failed to provide consistent results both on the cerebral substrates underlying cognitive deficits and on the effect of treatment on these anomalies. The aims of the study were a) to investigate whether never-treated OSA patients demonstrat- ed differences in brain activation compared to healthy controls during a cognitive task; and b) to investigate whether any improvements in cognitive functioning found in OSA patients after treatment reflected a change in the underlying cerebral activity. Design : OSA patients and healthy controls underwent functional mag- netic resonance imaging (fMRI) scanning. They were compared on per- formance and brain activation during a 2-back working-memory task. Patients were also re-evaluated after 3 months treatment with PAP. Cognitive functions were evaluated using neurocognitive tests. Sleepi- ness (ESS), mood (Beck Depression Inventory) and, quality-of-life (SF- 36) were also assessed. setting : The Sleep Disorders Center and CERMAC at the Vita-Salute San Raffaele University. Patients or Participants : 17 OSA patients and 15 age- and education- matched healthy controls. interventions : PAP treatment for 3 months. Measurements and results : Compared to controls, never-treated OSA patients showed increased activations in the left frontal cortex, medial precuneus, and hippocampus, and decreased activations in the caudal pons. OSA patients showed decreases in activation with treat- ment in the left inferior frontal gyrus and anterior cingulate cortex, and bilaterally in the hippocampus. Most neurocognitive domains, impaired at baseline, showed significant improvement after treatment. conclusions : OSA patients showed an overrecruitment of brain re- gions compared to controls, in the presence of the same level of performance on a working-memory task. Decreases of activation in prefrontal and hippocampal structures were observed after treatment in comparison to baseline. These findings may reflect a neural com - pensation mechanism in never-treated patients, which is reduced by

Patient characteristics associated with improved outcomes with use of an inhaled corticosteroid in preschool children at risk for asthma

Abstract: Background Maintenance inhaled corticosteroid (ICS) therapy in preschool children with recurrent wheezing at high-risk for development of asthma produces multiple clinical benefits. However, determination of baseline features associated with ICS responsiveness may identify children most likely to benefit from ICS treatment. Objective To determine if demographic and atopic features predict response to ICS in preschool children at high risk for asthma. Methods Two years of treatment with an ICS, fluticasone propionate (88 μg twice daily), was compared with matching placebo in a double-masked, randomized, multicenter study of 285 children 2 and 3 years old at high risk for asthma development. Baseline demographic and atopic features were related to clinical outcomes in a post hoc subgroup analysis. Results Multivariate analysis demonstrated significantly greater improvement with fluticasone than placebo in terms of episode-free days among boys, white subjects, participants with an emergency department (ED) visit or hospitalization within the past year, and those who experienced more symptomatic days at baseline. Children with aeroallergen sensitization experienced greater benefits in terms of oral corticosteroid use, urgent care and ED visits, and use of supplemental controller medications. Conclusions More favorable responses to ICS than placebo in high-risk preschool children over a 2-year period were more likely in those with a ED visit or hospitalization for asthma within the past year, children with aeroallergen sensitization, boys, and white subjects.

Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality.

Abstract: Rationale: Extracellular superoxide dismutase (EC-SOD) is a potent antioxidant that plays an important role in controlling oxidant-mediated stress and inflammation. High levels of EC-SOD are found in the lung. Acute lung injury (ALI) frequently occurs in patients with infection, and levels of EC-SOD have been shown to modulate severity of lung injury in transgenic animal models of endotoxemia-induced ALI. An R213G single nucleotide polymorphism (SNP) has been shown to alter levels of EC-SOD and patient outcomes in chronic obstructive pulmonary disease (COPD) and ischemic heart disease. Objectives: To determine genetic variation in the promoter and EC-SOD gene and to examine whether EC-SOD haplotype blocks are associated with clinical outcomes. Methods: We sequenced the EC-SOD promoter and gene to determine genetic variation and linkage disequilibrium (LD) patterns in a European American population. Two separate patient populations with infection-associated ALI were also evaluated to determine whether EC-SOD haplotypes were associated with clinical outcomes. Measurements and Main Results: Sequencing resulted in the identification of 28 SNPs with relatively strong LD and 1 block consisting of 4691-5321-5360-5955-5982. This specific block was shown to be protective in two separate patient populations with infection associated ALI. In particular, patients with a GCCT haplotype had a reduced risk of time on the ventilator and mortality. Conclusions: These results indicate that a GCCT haplotype may reduce inflammation in the lung, thereby decreasing the severity of lung injury and ultimately protecting patients from mortality associated with infection-induced ALI.

Lack of toxicity of a STAT3 decoy oligonucleotide.

Abstract: Background STAT3 overexpression has been detected in several cancers including head and neck squamous cell carcinoma (HNSCC). Previous studies using intratumoral administration of a STAT3 decoy oligonucleotide that abrogates STAT3-mediated gene transcription in preclinical cancer models have demonstrated antitumor efficacy. This study was conducted to observe the toxicity and biologic effects of the STAT3 decoy in a non-human primate model, in anticipation of initiating a clinical trial in HNSCC patients.

Symptom perception in children with asthma: cognitive and psychological factors.

Abstract: Objective: This study tested the differential effects of several cognitive and psychological variables on children's perception of asthma symptoms by use of an Asthma Risk Grid. Children's subjective and objective assessments of PEFR (peak expiratory flow rate) were characterized as representing perceptual accuracy, symptom magnification, and/or underestimation of asthma symptoms.

Fatal anaphylaxis to foods: epidemiology, recognition, and prevention.

Abstract: The inability to accurately predict the severity of future allergic reactions to foods in a given individual coupled with the real--although usually remote--risk of a fatal anaphylactic reaction complicates care and remains a constant source of concern to food-allergic patients, their family members, and health care providers. Current epidemiologic evidence suggests that the incidence of food-induced anaphylaxis is increasing, although confidently approximating the incidence of fatal allergic reactions to foods remains difficult. This article briefly reviews the epidemiology of fatal anaphylactic reactions to foods, discusses factors that may aid in identifying individuals at higher risk, emphasizes important aspects of patient education and prevention, and touches on the psychological impact of having a family member with food allergy.

Integrating health status and survival data: the palliative effect of lung volume reduction surgery.

Abstract: Rationale: In studies that address health-related quality of life (QoL) and survival, subjects who die are usually censored from QoL assessments. This practice tends to inflate the apparent benefits of interventions with a high risk of mortality. Assessing a composite QoL-death outcome is a potential solution to this problem. Objectives:Todeterminetheeffectoflungvolumereductionsurgery (LVRS) on a composite endpoint consisting of the occurrence of deathoraclinicallymeaningfuldeclineinQoLdefinedasanincrease of at leasteight points in the St. George’s Respiratory Questionnaire total score from the National Emphysema Treatment Trial. Methods:Inpatientswithchronicobstructivepulmonarydiseaseand emphysema randomized to receive medical treatment (n 5 610) or LVRS(n 5608),weanalyzedthesurvivaltothecompositeendpoint, thehazardfunctionsandconstructedpredictionmodelsoftheslope of QoL decline. Measurements and Main Results: The time to the composite endpoint was longer in the LVRS group (2 years) than the medical treatment group (1 year) (P , 0.0001). It was even longer in the subsets of patients undergoing LVRS without a high risk for perioperative death and with upper-lobe-predominant emphysema. The hazard for the composite event significantly favored the LVRS group, although it was most significant in patients with predominantly upper-lobe emphysema. The beneficial impact of LVRS on QoL decline was most significant during the 2 years after LVRS. Conclusions: LVRS has a significant effect on the composite QoLsurvival endpoint tested, indicating its meaningful palliative role, particularly in patients with upper-lobe‐predominant emphysema.

SP-A preserves airway homeostasis during Mycoplasma pneumoniae infection in mice

Abstract: The lung is constantly challenged during normal breathing by a myriad of environmental irritants and infectious insults. Pulmonary host defense mechanisms maintain homeostasis between inhibition/clearance of pathogens and regulation of inflammatory responses that could injure the airway epithelium. One component of this defense mechanism, surfactant protein-A (SP-A), exerts multifunctional roles in mediating host responses to inflammatory and infectious agents. SP-A has a bacteriostatic effect on Mycoplasma pneumoniae (Mp), which occurs by binding surface disaturated phosphatidylglycerols. SP-A can also bind the Mp membrane protein, MPN372. In this study, we investigated the role of SP-A during acute phase pulmonary infection with Mp using mice deficient in SP-A. Biologic responses, inflammation, and cellular infiltration, were much greater in Mp infected SP-A −/− mice than wild-type mice. Likewise, physiologic responses (airway hyperresponsiveness and lung compliance) to Mp infection were more severely affected in SP-A −/− mice. Both Mp-induced biologic and physiologic changes were attenuated by pharmacologic inhibition of TNF-α. Our findings demonstrate that SP-A is vital to preserving lung homeostasis and host defense to this clinically relevant strain of Mp by curtailing inflammatory cell recruitment and limiting an overzealous TNF-α response.

Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor

Abstract: Background—Recent studies have identified a polymorphism in the endothelin-converting enzyme (ECE)–1b promoter (338C/A) that is strongly associated with hypertension in women. The polymorphism is located in a consensus binding sequence for the E2F family of transcription factors. E2F proteins are crucially involved in cell-cycle regulation, but their roles in cardiovascular function are poorly understood. Here, we investigated the potential role of E2F2 in blood pressure regulation. Methods and Results—Tail-cuff measurements of systolic and diastolic blood pressures were significantly higher in E2F2-null (E2F2 / ) mice than in their wild-type littermates, and in ex vivo ring assays, aortas from the E2F2 / mice exhibited significantly greater contractility in response to big endothelin-1. Big endothelin-1 is activated by ECE-1, and mRNA levels of ECE-1b, the repressive ECE-1 isoform, were significantly lower in E2F2 / mice than in wild-type mice. In endothelial cells, chromatin immunoprecipitation assays confirmed that E2F2 binds the ECE-1b promoter, and promoter-reporter assays indicated that E2F2 activates ECE-1b transcription. Furthermore, loss or downregulation of E2F2 led to a decline in ECE-1b levels, to higher levels of the membranous ECE-1 isoforms (ie, ECE-1a, -1c, and -1d), and to deregulated ECE-1 activity. Finally, Sam68 coimmunoprecipitated with E2F2, occupied the ECE-1b promoter (chromatin immunoprecipitation), and repressed E2F2-mediated ECE-1b promoter activity (promoter-reporter assays). Conclusion—Our results identify a cell-cycle–independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure. (Circulation. 2009;120:1213-1221.)

Postnatal Estradiol Up-regulates Lung Nitric Oxide Synthases and Improves Lung Function in Bronchopulmonary Dysplasia

Abstract: Rationale: Nitric oxide (NO) plays an important role in lung development and perinatal lung function, and pulmonary NO synthases (NOS) are decreased in bronchopulmonary dysplasia (BPD) following preterm birth. Fetal estradiol levels increase during late gestation and estradiol up-regulates NOS, suggesting that after preterm birth estradiol deprivation causes attenuated lung NOS resulting in impaired pulmonary function. Objective: To test the effects of postnatal estradiol administration in a primate model of BPD over 14 days after delivery at 125 days of gestation (term = 185 d). Methods: Cardiopulmonary function was assessed by echocardiography and whole body plethysmography. Lung morphometric and histopathologic analyses were performed, and NOS enzymatic activity and abundance were measured. Measurements and Main Results: Estradiol caused an increase in blood pressure and ductus arteriosus closure. Expiratory resistance and lung compliance were also improved, and this occurred before spontaneous ductal closure. Furthermore, both oxygenation and ventilation indices were improved with estradiol, and the changes in lung function and ventilatory support requirements persisted throughout the study period. Whereas estradiol had negligible effect on indicators of lung inflammation and on lung structure assessed after the initial 14 days of ventilatory support, it caused an increase in lung neuronal and endothelial NOS enzymatic activity. Conclusions: In a primate model of BPD, postnatal estradiol treatment had favorable cardiovascular impact, enhanced pulmonary function, and lowered requirements for ventilatory support in association with an up-regulation of lung NOS. Estradiol may be an efficacious postnatal therapy to improve lung function and outcome in preterm infants.

Heritability of Lung Function in Severe Alpha-1 Antitrypsin Deficiency

Abstract: Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial agg

Pattern Recognition in Phagocytic Clearance of Altered Self

Abstract: Cells that are unnecessary or harmful to our body emerge in substantial numbers throughout our life. Such “unwanted” cells need to be promptly and selectively removed for tissue homeostasis to be maintained. Most of those cells are induced to undergo physiologic cell death, i.e., apoptosis, and subsequently eliminated by phagocytosis. Target selectivity in this phagocytosis reaction comes from the specific cell-cell interaction between phagocytes and dying cells. The surface structure of apoptotic cells is altered during the death pathway so that they become pattern recognizable as “altered self” by phagocytes, and such surface structures are sometimes called ACAMPs for apoptotic cell-associated molecular patterns. ACAMPs arise either from the exofacial exposure of endogenous molecules or the modification of preexisting surface molecules. Pattern-recognizing phagocytosis receptors present at the surface of phagocytes specifically bind, either directly or indirectly with an aid of bridge molecules, to ACAMPs and transmit signals to induce phagocytosis of bound apoptotic cells. Phagocytes often evoke subsequent actions, rather than simply digesting engulfed apoptotic cells, for a finer tuning of tissue homeostasis. In contrast, precise mechanisms and consequences of cells undergoing nonapoptotic death, i.e., necrosis or autophagy-related death, are less well understood.

Assessment of apoptotic cell phagocytosis by macrophages.

Abstract: Cells undergo apoptosis during development, tissue homeostasis, and disease, and are rapidly cleared by both professional and nonprofessional phagocytes. In the whole animal, this process is remarkably efficient and usually goes unnoticed. It is estimated that 2 x 10(11) cells are cleared each day and it has been suggested that detection of apoptotic cells in tissues should lead one to at least question the presence of a local clearance defect. For the last two decades, in vitro phagocytosis assays have played a critical role in identifying the receptors and mechanisms involved in the recognition and ingestion of apoptotic cells. The methodology of phagocytosis assays can be broken down into four separate components: apoptosis induction in target cells, preparation of phagocytes, the interaction assay, and the quantitative assessment of apoptotic cell engulfment. Here, we attempt to provide a detailed description of all the individual components of this complex procedure. To date, this has not been done in its entirety but is vital for the accurate assessment of stimuli that influence the clearance process.

Antigen-restricted γδ T-cell receptors?

Abstract: After more than two decades of investigation, the biological role of the γδ T-cell receptors (TCRs) remains elusive. In fact, a theory of ligand recognition is still lacking that accounts for their adaptable structure, their peripheral selection, and the observed responses of γδ T cells, which do not require immunization but only include cells sharing germline-encoded components of the TCR. Assuming that all γδ T cells recognize ligands by a common mechanism, we now propose that germline-encoded components of the γδ TCRs provide for the specific recognition of a select set of antigenic determinants (Ags) which appear on the cell surface in various molecular associations. Furthermore, we hypothesize that the adaptivity of the γδ TCRs serves to increase affinity for the molecules with which these Ags associate rather than for the Ags themselves. Here we outline this hypothetical mechanism and discuss its possible implications for thymic selection and potential for complementing known innate and adaptive mechanisms of immune defense.

MHC-dependent desensitization of intrinsic anti-self reactivity

Abstract: The survival of naive T cells is compromised in the absence of molecules encoded by the major histocompatibility complex (MHC) while antigen-experienced T cells survive. We hypothesized that survival pressures in an in vivo, MHC-deficient environment would permit enrichment of less frequent antigen-experienced autoreactive cells at the expense of the majority of antigen naive T cells. To test this hypothesis, we generated MHC class I- and class II-deficient mice in NOD and C57Bl/6 (B6) backgrounds, and examined the capacity of adoptively transferred autoimmune-prone NOD T cells, or non-autoimmune prone naive B6 T cells, respectively, to reject transplanted wild-type pancreatic islets or transplantable tumors in the MHC-deficient mice. In the MHC-deficient environment, CD4 T cells acquired self-hostile properties (islet rejection and tumor invasion) that were independent from their genetic propensity for autoreactivity, while CD8 T cells required appropriate prior exposure to antigen in order to survive and function (reject tumor) in this environment; however, disengagement of Tob1, a negative regulator of proliferation, led to a reverse phenotype with regard to persistence of CD4 and CD8 T cells in the MHC-deficient environment. Our data suggest that self-peptide/MHC interactions have dual roles to facilitate survival and restrain autoreactivity, thus acting as integral components of an intrinsic network of negative regulation that maintains tolerance.

Drug Resistance Assays for Mycobacterium tuberculosis

Abstract: The introduction of antimicrobial therapy of tuberculosis during the second half of the last century was a turning point in the millennium-old history of this disease. However, the problem of drug resistance emerged, and with it, two levels of concern. First, such resistance not only poses a public health threat to successful control of TB epidemics, but it also complicates the approach to treatment of individual patients. In previous reviews we have addressed the history of research and evolution of views based on these studies

Measurement and analysis of leukotrienes

Abstract: The present invention provides a new analytical method for measuring leukotrienes in a clinical sample using liquid chromatography and tandem mass spectrometry (LCMSMS). The method provides a simple, rapid and low-cost assay for the measurement of leukotriene levels in a clinical sample with high accuracy and precision over the physiological range. The present invention further provides a method to determine the susceptibility of a subject to treatment with a leukotriene modifier, as wells as methods for diagnosis of a chronic obstructive disease of the airways and for predicting the risk of exacerbation of the same.

Methods for Treatment and Diagnosis of Pulmonary Diseases Based on the Expression of SERCA2 Protein

Abstract: The present invention is directed to methods of treatment of cystic fibrosis. The invention includes a method for treatment of cystic fibrosis in a patient by increasing the activity of sarcoendoplasmic reticulum calcium ATPase (SERCA) in a patient. More specifically, the step of increasing SERCA activity can include but is not limited to, administration of SERCA protein or its homologues, gene therapy to restore or enhance SERCA activity, or the administration of compounds stimulating the activity of endogenous SERCA. Reference herein to SERCA, can include in preferred embodiments, the isoform SERCA2, which is the principal lung isoform of SERCA. The present invention is based on the finding that SERCA2 (a calcium pump) is deficient (not 100%) in the lung epithelial cells of cystic fibrosis samples.

Antiretroviral treatment interruptions and risk of non-opportunistic diseases

Abstract: Structured treatment interruptions have been studied as a strategy to reduce antiretroviral toxicities and expenditures in the treatment of HIV-infected individuals. Paradoxically, in addition to the increased incidence of death and opportunistic infections, these interruptions in therapy have resulted in the development of a number of non-opportunistic diseases, including cardiovascular events, renal insufficiency, hepatic failure, and non-AIDS-defining malignancies. Hypotheses regarding these findings suggest that the augmented stimulation of the host response to unabated viral replication may contribute to these comorbidities. Increased expression of chemokine receptor 5 and proinflammatory cytokines, disruption of immune cell function, and reduction in key inflammatory cells have been studied as potential mechanisms. Additionally, the increased inflammatory response has been shown to increase intracellular levels of nucleoside and nucleotide reverse transcriptase inhibitors, resulting in increased toxic manifestations. Structured treatment interruptions should be avoided in the management of HIV-infected individuals.

CD8+ T Cells Play a Key Role in the Development of Allergic Lung Inflammation

Abstract: Asthma is a complex syndrome involving many cell types, effector molecules, and mediators. CD4+ T cells are known to play a pivotal role in the initiation of the disease. Here, the role of the CD8+ T cells is highlighted, both in the triggering of lung allergic responses and in the negative regulation of these responses.