D A Schwartz

..The significance of Th-1 and Th-2 lymphocyte-mediated immunity are discussed, and the inflammatory processes leading to chronic airway inflammation are detailed...

..Moreover, exploiting eukaryotic model systems (yeast, Caenorhabditis elegans, zebrafish, Drosophila and rodents) will accelerate our understanding of environmental exposures on human health...

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..We recently identified a common polymorphism in toll-like receptor 4 (TLR4) that is associated with hyporesponsiveness to inhaled endotoxin or lipopolysaccharide in humans...

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..These results suggest that LPS antagonists may be an effective and potentially safe treatment for endotoxin-induced airway disease...

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..05). These findings indicate that exogenous IL-10 is effective in reducing airway inflammation and airway hyperreactivity due to the inhalation of CDE...

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..We have developed and pursued the hypothesis that local activation of pulmonary innate immunity through toll-like receptor (TLR)-4 is critical to the development of posttransplant alloimmune lung injury...

..These findings demonstrate that an LPS phenotype can be reproducibly elicited in humans, which creates an opportunity to identify genes involved in this response to inhaled LPS...

..Because beta-arrestin-2 regulates the development of allergic inflammation at a proximal step in the inflammatory cascade, novel therapies focused on this protein may prove useful in the treatment of asthma...

..Testing of candidate genes and standards for formal proof of gene discovery are discussed...

..Our data demonstrate that the expression of beta-arrestin-2 in at least two divergent cell types contributes to the pathogenesis of allergic airway disease...

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..These results suggest that, although subjects with BHR develop a more precipitous decline in FEV(1) after exposure to CDE, the inflammatory response to CDE is similar in subjects with and without BHR...

..These findings suggest that bacterial DNA, and unmethylated CpG motifs in particular, may play an important pathogenic role in inflammatory lung disease...

..Our results indicate that endogenous SNOs, governed by GSNOR, are critical regulators of airway responsivity and may provide new therapeutic approaches to asthma...

..However, the relation between TLR4 and hyaluronan in the airway response to ozone remains unexplored...

..Our results also suggest that the frequency of such unidentified, spontaneously occurring mutations is an issue that should be considered when RI strains are used to identify QTL...

..More importantly, both of the subjects with the TLR2 Arg753Gln polymorphism had staphylococcal infections. These findings suggest that a mutation in the TLR2 gene may predispose individuals to life-threatening bacterial infections...

..This gives rise to the notion that LPS from some bacterial species will utilize alternative receptors to stimulate the innate immune response...

..Furthermore, these alterations in SP-A gene activity and protein metabolism are dependent on an intact endotoxin signaling system...

..Our findings demonstrate that subchronic inhalation of LPS results in the development of persistent airway disease in endotoxin-responsive mice...

..These results indicate that TNF-alpha and IL-1 beta do not appear to have an essential role in mediating the physiological or inflammatory response to inhaled LPS...

..A much larger study population would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans...

..These data disclose the dual role of TLR4 in mtDNA damage and compensatory mitochondrial biogenic responses after innate immune activation...

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..024, p = 0.028, respectively) or in premature multiples (p = 0.036, p = 0.044, respectively). According to the present results an allelic variation in the TLR4 receptor was associated with increased risk of premature birth...

..These unique problems must be considered in developing interventions that effectively reduce the morbidity and mortality of asthma in children from rural communities...

..Inhibition of innate immune activation through CD14 represents a novel and potentially important therapeutic target to prevent post-transplant rejection and improve outcomes after human lung transplantation...

..Therapies directed at inhibition of innate immune responses mediated by TLR4 may represent a novel and effective means to prevent acute rejection after lung transplantation...

..In addition, gene expression profiling data have revealed other potential novel targets for therapeutics-based research and has enhanced the understanding of the molecular mechanisms underlying the etiology of "asthma."..

..These genes could represent potential sepsis biomarkers or therapeutic targets that should be further investigated in human populations...

..These findings have resulted in new opportunities to study the pathogenesis of disease, identify subpopulations at greater risk of disease, and, potentially, identify novel therapeutic approaches...

..This article will discuss the key cellular and secreted components of the pulmonary innate immune system...

..These data demonstrate the critical role of hematopoietic cells and alveolar macrophages in initiating LPS-induced neutrophil recruitment from the vascular space to the airspace...

..Several lines of evidence suggest that genetic factors and environmental exposures play a role in the development of pulmonary fibrosis...

..The genetics of TLRs provides important insights in gene-environment interactions in health and disease, and it may enable scientists to assess patients' susceptibility to diseases or predict their response to treatments...

..5) induced a gene expression profile prevalent with genes related to metal binding and oxidative stress in human AMs, independent of oxidative stress. Metals associated with PM may play an important role in particle-induced gene changes...

..In the present investigation, we sought to evaluate the role of innate immune activation through TLR4, in either donor or recipient, upon the development of renal allograft rejection...

..These studies demonstrate that neutrophils play a critical role in the development of chronic LPS-induced airway disease...

..These findings may have clinical significance, because recent studies reported associations between surfactant protein polymorphisms and a variety of lung diseases...

..Cytokine polymorphisms are inconsistently associated with transplant rejection and other adverse outcomes. To address this controversy, we evaluated cytokine single nucleotide polymorphisms (SNPs) in a lung transplant cohort...

..In addition, CD44-deficient animals had 150% fewer neutrophils at 24 h and 50% greater neutrophils 48 h after LPS exposure. These results support the role of CD44 in modulating the biologic response to inhaled LPS...

..MicroCT pulmonary compliance measurements are suitable for longitudinal measurements, and correlate with physiologic measurements of pulmonary compliance...

..These results demonstrate that innate differences in pulmonary host defense to S. zooepidemicus are dependent on host genetic factors...

..The role of IL-10 on airway hyperreactivity is complex: IL-10 deficiency protects against LPS-induced hyperreactivity, and is associated with higher eNOS, iNOS, and airway nitrate levels...

..This novel function of IaI provides a mechanistic explanation for its observed salutary effects in sepsis and opens new possibilities for its use as a treatment agent in inflammatory diseases...

..Inhaled airway challenge using lipopolysaccharide in humans has been performed for over 20 years to assess the airway response to endotoxin. However, there are no published data on the short-term safety of endotoxin inhalation protocols...

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..We conclude from these findings that pitch entails an auditory process that relates inevitably ambiguous sound stimuli to their probable natural sources...

..Functional studies of these genes are expected to reveal important molecular mechanisms regulating the magnitude of biologic responses to LPS...

..These data demonstrate in the mouse that the requirement of TLR4 for pulmonary inflammation depends on the nature of the toxin and appears specific to toxin and exposure conditions...

..In aggregate, our approach has identified O3-resistant (C3H/HeJ and A/J) and -vulnerable (C57BL/6J and 129/SvIm) strains of mice, and determined novel genomic loci, suggesting a clear genetic basis for the lung response to inhaled O3...

..This analysis yielded a list of 212 genes in common suggesting that there is a common subset of genes that regulate fibroproliferation in the lung independent of etiologic agent and site of injury...

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..We conclude that an active fibrinolytic system can substantially alter the development and resolution of the postinflammatory airway remodeling observed after chronic LPS inhalation...

..Previous mechanistic research has focused on the local fibroproliferative process in the lung. However, emerging evidence suggests that circulating cells of hematopoietic origin play a crucial role in the pathogenesis of this disease...

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..These observations indicate that ozone exposure increases both the pulmonary and the systemic biologic response to inhaled LPS by priming the innate immune system...

..In this review, we provide a brief overview on the role of endotoxin in asthma and COPD, highlighting a few of the major discoveries, but also discussing future directions...

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..Our findings indicate that dietary factors can modify the heritable risk of allergic airway disease through epigenetic mechanisms during a vulnerable period of fetal development in mice...

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..As this body of data grows, it will provide new insights into disease pathogenesis as well as valuable information on the merits of various therapeutic options...

..Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection...

..Together, these findings show that low doses of endotoxin can have regulatory effects on allergic inflammation, particularly in the setting of ongoing allergen exposure...

..These genes may prove critical to understanding host defense and represent potential therapeutic targets for infectious and immunological diseases...

..Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression...

..In contrast, there was no association between the modeled exposure and any of the outcomes. These findings do not support speculation that exposures to oil-fire smoke caused respiratory symptoms among veterans...

..This improved understanding promises to facilitate the future development of novel therapies for many different inflammatory diseases including asthma, sepsis and atherosclerosis...

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..Lung biopsy is most helpful when clinical and radiologic data result in an uncertain diagnosis or when patients are thought not to have IPF...

..Cryptosporidium and Enterocytozoon were associated with malnutrition. Asymptomatic fecal shedding of Enterocytozoon in otherwise healthy, HIV children has not been described previously...

..Current smoking was associated with lower IL-1 beta and IL-1ra release in ILD. The IL-1AI is a convenient method for comparison of IL-1 beta activity between patient populations...

..We determined whether recently discovered genetic variants of toll-like receptor 4 (TLR4) that confer differences in the inflammatory response elicited by bacterial lipopolysaccharide are related to the development of atherosclerosis...

..These findings suggest that CD11b and ICAM-1 are important mediators of LPS-induced airway inflammation, but do not appear to be critical to the development of LPS-induced airway hyperreactivity...

..These findings suggest that certain sequences in a gene or a cluster of genes in the 129 mouse strain impart a phenotype in which there is a delay in, or protection from, the development of lung fibrogenesis...

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..This would reduce the number of patients undergoing DXA testing unnecessarily. We tried to determine if calcaneal ultrasound bone densitometry is a useful tool in screening high-risk patients with IBD for metabolic bone disease...

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..Both the genetics and the histologic type of IIP play a role in the etiology and pathogenesis of interstitial lung disease, but transcriptional signatures of these subtypes are unknown...

..These data suggest that the response to O2 depends, in part, on the genetic background and that some of the strains analyzed can be used to identify specific loci and genes underlying the response to O2...

..The contribution of IL-1beta signaling through the IL-1 type 1 receptor (IL-1R1) to the development of persistent LPS-induced airway disease has not been investigated...

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