There is increasing data implicating inflammatory mediators such as leukotrienes as playing pivotal roles in asthma. Inflammation is normally a """"""""self-limited"""""""" process. Chalones of inflammation serve as endogenous molecules with the capacity to down regulate inflammatory responses. Although we have become accustomed to thinking about diseases such as asthma as reflective of a micro-environmental excess of pro-inflammatory molecules, it is also possible that a similar pathological state could derive from a loss of endogenous down-regulatory species. In work in progress, we have isolated a series of novel lipid-derived chalones (NLC), the 15-epimer lipoxins (LX), which prevent adhesion of neutrophils (PMN) to vascular endothelial cells at nanomolar concentrations. Since recruitment of leukocytes into the lung must occur originally at the level of the pulmonary microvasculature, we will test the following hypothesis in this SCOR proposal: In normal and non-asthmatic atopic individuals, 15-epimeric LX and lX are generated predominantly by transcellular biosynthesis and function together as endogenous chalones to limit the adhesion of inflammatory cells (eosinophils and neutrophils) to the pulmonary microvasculature, this molecular mechanism of inflammatory damping is diminished in patients with asthma.
The aims are to: 1) Document the biosynthesis of NLC during cell-cell interactions between neutrophils (PMN)-endothelial cells vs. PMN-alveolar epithelial cells. A second series will focus on PMN from healthy, atopic and asthmatic-donors for their ability to generate NLC alone and by transcellular biosynthetic routes. 2) Evaluate the formation of NLC by eosinophil-lung epithelial cell and lung endothelial cell interactions. Focus will be on establishing the role of cyclooxgenase II, lipoxygenase and/or P450 biosynthetic routes in these cells and the role of selected cytokines tested. 3) Test bioactions of NLC. We will establish structure activity relationships (SARs) for PMN and eosinophil inhibition by NLC. A second series will focus on NLC regulation of leukocyte interactions with both alveolar epithelial cells and lung-derived endothelial cells. Labeled ligands will be prepared and used to determine the site)s) of action for these NLC with these cell types. 4) Profile of NLC and mediators in asthmatics. In order for NLC or other eicosanoids to play pivotal roles, they must be generated in quantities sufficient to evoke responses. To this end we will monitor generation of NLC, LX and LT in normal, non-asthmatic atopic subjects and asthmatics in bronchoalveolar lavage and urine and evaluate the impact of current modes of therapy. These studies are expected to provide direct evidence for new mediators (i.e., NLC) in asthma and their relationship to known """"""""proinflammatory"""""""" agents. The long-term goal is to understand the contributions of lipid mediators to pulmonary disorders.
| Storm van's Gravesande, Karin; Wechsler, Michael E; Grasemann, Hartmut et al. (2003) Association of a missense mutation in the NOS3 gene with exhaled nitric oxide levels. Am J Respir Crit Care Med 168:228-31 |
| Shore, Stephanie A; Moore, Paul E (2003) Regulation of beta-adrenergic responses in airway smooth muscle. Respir Physiol Neurobiol 137:179-95 |
| Levy, Bruce D; De Sanctis, George T; Devchand, Pallavi R et al. (2003) Lipoxins and aspirin-triggered lipoxins in airway responses. Adv Exp Med Biol 525:19-23 |
| Baraldo, Simonetta; Faffe, Deborah S; Moore, Paul E et al. (2003) Interleukin-9 influences chemokine release in airway smooth muscle: role of ERK. Am J Physiol Lung Cell Mol Physiol 284:L1093-102 |
| Moore, Paul E; Calder, Mark M; Silverman, Eric S et al. (2003) Effect of dexamethasone on beta2-adrenergic desensitization in airway smooth muscle: role of the ARG19 polymorphism. Chest 123:368S-9S |
| Shore, Stephanie A (2002) Cytokine regulation of beta-adrenergic responses in airway smooth muscle. J Allergy Clin Immunol 110:S255-60 |
| Shore, Stephanie A; Moore, Paul E (2002) Effects of cytokines on contractile and dilator responses of airway smooth muscle. Clin Exp Pharmacol Physiol 29:859-66 |
| Silverman, Edwin K; Mosley, Jonathan D; Palmer, Lyle J et al. (2002) Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes. Hum Mol Genet 11:623-32 |
| Lahiri, Thomas; Moore, Paul E; Baraldo, Simonetta et al. (2002) Effect of IL-1beta on CRE-dependent gene expression in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 283:L1239-46 |
| Silverman, Edwin K; Palmer, Lyle J; Mosley, Jonathan D et al. (2002) Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease. Am J Hum Genet 70:1229-39 |
Showing the most recent 10 out of 46 publications
