Background-Single nucleotide polymorphisms in the human gene for the receptor for advanced glycation end products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of type 2 cytokines, IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the pro-allergic cytokine, IL-33.

Asthma is a common respiratory disease affecting approximately 300 million people worldwide. Airway inflammation is thought to contribute to asthma pathogenesis, but the direct relationship between inflammation and airway hyperresponsiveness remains unclear. This study investigates the role of inflammation in a steroid-insensitive, severe allergic airway disease model and in severe asthmatics stratified by inflammatory profile. First, we utilized the TH17 cell adoptive transfer mouse model of asthma to induce pulmonary inflammation, which was lessened by TNFα neutralization or neutrophil depletion. While decreased airspace inflammation following TNFα neutralization and neutrophil depletion rescued lung compliance, neither intervention improved airway hyperresponsiveness to methacholine, and tissue inflammation remained elevated when compared to control. Further, sputum samples were collected and analyzed from 41 severe asthmatics. In severe asthmatics with elevated levels of sputum neutrophils, but low levels of eosinophils, increased inflammatory markers did not correlate with worsened lung function. This subset of asthmatics also had significantly higher levels of TH17-related cytokines in their sputum compared to other severe asthmatics with other inflammatory phenotypes. Overall, this work suggests that lung compliance may be linked with cellular inflammation in the airspace, while T cell-driven airway hyperresponsiveness may be associated with tissue inflammation and other pulmonary factors.

Asbestosis is a form of interstitial lung disease caused by the inhalation of asbestos fibers, leading to inflammation and pulmonary fibrosis. Inflammation and oxidant/antioxidant imbalances are known to contribute to the disease pathogenesis. Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme that has been shown to protect the lung from oxidant-mediated damage, inflammation, and interstitial fibrosis. Extracellular matrix (ECM) components, such as collagen and glycosaminoglycans, are known to be sensitive to oxidative fragmentation. Heparan sulfate, a glycosaminoglycan, is highly abundant in the ECM and tightly binds EC-SOD. We investigated the protective role of EC-SOD by evaluating the interaction of EC-SOD with heparan sulfate in the presence of reactive oxygen species (ROS). We found that ROS-induced heparin and heparan sulfate fragments induced neutrophil chemotaxis across a modified Boyden chamber, which was inhibited by the presence of EC-SOD by scavenging oxygen radicals. Chemotaxis in response to oxidatively fragmented heparin was mediated by Toll-like receptor-4. In vivo, bronchoalveolar lavage fluid from EC-SOD knockout mice at 1, 14, and 28 days after asbestos exposure showed increased heparan sulfate shedding from the lung parenchyma. We demonstrate that one mechanism through which EC-SOD inhibits lung inflammation and fibrosis in asbestosis is by protecting heparin/heparan sulfate from oxidative fragmentation.

The Th17 pathway has recently been shown to play a critical role in host defense, allergic responses and autoimmune inflammation. Th17 cells predominantly produce IL-17 and IL-22, which are two cytokines with broad effects in the lung and other tissues. This review summarizes not only what is currently known about the molecular regulation of this pathway and Th17-related cytokine signaling, but also the roles of these cytokines in pathogen immunity and asthma. In the last 5 years, the Th17 field has rapidly grown and research has revealed that the Th17 pathway is essential in lung pathogenesis in response to exogenous stimuli. As work in the field continues, it is expected that many exciting therapeutic advances will be made for a broad range of diseases.

Fifty-nine RNA duplexes containing single nucleotide bulge loops were optically melted in 1M NaCl, and the thermodynamic parameters ΔH°, ΔS°, ΔG°3 7 , and T M for each sequence were determined. Sequences from this study were combined with sequences from previous studies (Longfellow et al., (1990) Biochemistry 29, 278-285 andZnosko et al., (2002) Biochemistry 41, 10406-10417), thus examining all possible group I single nucleotide bulge loop and nearest-neighbor sequence combinations. The free energy increments at 37 °C for the introduction of a group I single nucleotide bulge loop ranges between 1.3 and 5.2 kcal/mol. The combined data were used to develop a model to predict the free energy of an RNA duplex containing a single nucleotide bulge. For bulge loops with adjacent Watson-Crick base pairs, neither the identity of the bulge nor the nearest-neighbor base pairs had an effect on the influence of the bulge loop on duplex stability. The proposed model for prediction of the stability of a duplex containing a bulged nucleotide was primarily affected by non-nearestneighbor interactions. The destabilization of the duplex by the bulge was related to the stability of the stems adjacent to the bulge. Specifically, there was a direct correlation between the destabilization of the duplex and the stability of the less stable duplex stem. The stability of a duplex containing a bulged nucleotide adjacent to a wobble base pair also was primarily affected by non-nearest-neighbor interactions. Again, there was a direct correlation between the destabilization of the duplex and the stability of the less stable duplex stem. However, when one or both of the bulge nearest neighbors was a wobble base pair, the free energy increment for insertion of a bulge loop is dependent upon the position and orientation of the wobble base pair relative the bulged nucleotide. Bulge sequences of the type , , and are less destabilizing by 0.6 kcal/mol and bulge sequences of the type and are more destabilizing by 0.4 kcal/mol than bulge loops adjacent to Watson-Crick base pairs.RNA fulfills essential cellular roles including storage of information, protein and small molecule binding, and chemical catalysis (1-10). The functional diversity of RNA is often predicated by hierarchical folding of complex tertiary structures with secondary structure formation preceding that of the native, functional fold (11,12). Since the tertiary structure arises from the preformed secondary structure, accurately determining the secondary structure of an