Discovery of a potent nanoparticle P‐selectin antagonist with anti‐inflammatory effects in allergic airway disease

The severity of allergic asthma is dependent, in part, on the intensity of peribronchial inflammation. P‐selectin is known to play a role in the development of allergen‐induced peribronchial inflammation and airway hyperreactivity. Selective inhibitors of P‐selectin‐ mediated leukocyte endothelial‐cell interactions may therefore attenuate the inflammatory processes associated with allergic airway disease. Novel P‐selectin inhibitors were created using a polyvalent polymer nanoparticle capable of displaying multiple synthetic, low molecular weight ligands. By assembling a particle that presents an array of groups, which as monomers interact with only low affinity, we created a construct that binds extremely efficiently to P‐ selectin. The ligands acted as mimetics of the key binding elements responsible for the high‐ avidity adhesion of P‐selectin to the physiologic ligand, PSGL‐1. The inhibitors were initially evaluated using an in vitro shear assay system in which interactions between circulating cells and P‐selectin‐coated capillary tubes were measured. The nanoparticles were shown to preferentially bind to selectins expressed on activated endothelial cells. We subsequently demonstrated that nanoparticles displaying P‐selectin blocking arrays were functionally active in vivo, significantly reducing allergen‐induced airway hyperreactivity and peribronchial eosinophilic inflammation in a murine model of asthma.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154265/1/fsb2fj030166fje-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154265/2/fsb2fj030166fje.pd

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154665/1/fsb2fj078653com.pd

Scalar Field Quantization Without Divergences In All Spacetime Dimensions

Covariant, self-interacting scalar quantum field theories admit solutions for low enough spacetime dimensions, but when additional divergences appear in higher dimensions, the traditional approach leads to results, such as triviality, that are less than satisfactory. Guided by idealized but soluble {\it non}renormalizable models, a nontraditional proposal for the quantization of covariant scalar field theories is advanced, which achieves a term-by-term, divergence-free, perturbation analysis of interacting models expanded about a suitable pseudofree theory, which differs from a free theory by an O(\hbar^2) counterterm. These positive features are realized within a functional integral formulation by a local, nonclassical, counterterm that effectively transforms parameter changes in the action from generating mutually singular measures, which are the basis for divergences, to equivalent measures, thereby removing all divergences. The use of an alternative model about which to perturb is already supported by properties of the classical theory, and is allowed by the inherent ambiguity in the quantization process itself. This procedure not only provides acceptable solutions for models for which no acceptable, faithful solution currently exists, e.g., \phi^4_n, for spacetime dimensions n\ge4, but offers a new, divergence-free solution, for less-singular models as well, e.g., \phi^4_n, for n=2,3. Our analysis implies similar properties for multicomponent scalar models, such as those associated with the Higgs model.Comment: 45 pages, has relevance for the Higgs model, review and updated analysis, version accepted for publicatio

A Novel Inactivated Intranasal Respiratory Syncytial Virus Vaccine Promotes Viral Clearance without Th2 Associated Vaccine-Enhanced Disease

Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and pneumonia in young children worldwide, and no vaccine is currently available. Inactivated RSV vaccines tested in the 1960's led to vaccine-enhanced disease upon viral challenge, which has undermined RSV vaccine development. RSV infection is increasingly being recognized as an important pathogen in the elderly, as well as other individuals with compromised pulmonary immunity. A safe and effective inactivated RSV vaccine would be of tremendous therapeutic benefit to many of these populations.In these preclinical studies, a mouse model was utilized to assess the efficacy of a novel, nanoemulsion-adjuvanted, inactivated mucosal RSV vaccine. Our results demonstrate that NE-RSV immunization induced durable, RSV-specific humoral responses, both systemically and in the lungs. Vaccinated mice exhibited increased protection against subsequent live viral challenge, which was associated with an enhanced Th1/Th17 response. In these studies, NE-RSV vaccinated mice displayed no evidence of Th2 mediated immunopotentiation, as has been previously described for other inactivated RSV vaccines.These studies indicate that nanoemulsion-based inactivated RSV vaccination can augment viral-specific immunity, decrease mucus production and increase viral clearance, without evidence of Th2 immune mediated pathology

Chemokines and their role in airway hyper-reactivity

Airway hyper-reactivity is a characteristic feature of many inflammatory lung diseases and is defined as an exaggerated degree of airway narrowing. Chemokines and their receptors are involved in several pathological processes that are believed to contribute to airway hyper-responsiveness, including recruitment and activation of inflammatory cells, collagen deposition and airway wall remodeling. These proteins are therefore thought to represent important therapeutic targets in the treatment of airway hyper-responsiveness. This review highlights the processes thought to be involved in airway hyper-responsiveness in allergic asthma, and the role of chemokines in these processes. Overall, the application of chemokines to the prevention or treatment of airway hyper-reactivity has tremendous potential

Airway smooth muscle as an immunomodulatory cell.

Although pivotal in regulating bronchomotor tone in asthma, airway smooth muscle (ASM) also modulates airway inflammation in asthma. ASM myocytes secrete or express a wide array of immunomodulatory mediators in response to extracellular stimuli, and in chronic severe asthma, increases in ASM mass may also render the airway irreversibly obstructed. Although the mechanisms by which ASM secretes cytokines and chemokines are shared with those regulating immune cells, there exist unique ASM signaling pathways that may provide novel therapeutic targets. This review provides an overview of our current understanding of the proliferative as well as synthetic properties of ASM

A Chaperone Trap Contributes to the Onset of Cystic Fibrosis

Protein folding is the primary role of proteostasis network (PN) where chaperone interactions with client proteins determine the success or failure of the folding reaction in the cell. We now address how the Phe508 deletion in the NBD1 domain of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein responsible for cystic fibrosis (CF) impacts the binding of CFTR with cellular chaperones. We applied single ion reaction monitoring mass spectrometry (SRM-MS) to quantitatively characterize the stoichiometry of the heat shock proteins (Hsps) in CFTR folding intermediates in vivo and mapped the sites of interaction of the NBD1 domain of CFTR with Hsp90 in vitro. Unlike folding of WT-CFTR, we now demonstrate the presence of ΔF508-CFTR in a stalled folding intermediate in stoichiometric association with the core Hsps 40, 70 and 90, referred to as a ‘chaperone trap’. Culturing cells at 30 C resulted in correction of ΔF508-CFTR trafficking and function, restoring the sub-stoichiometric association of core Hsps observed for WT-CFTR. These results support the interpretation that ΔF508-CFTR is restricted to a chaperone-bound folding intermediate, a state that may contribute to its loss of trafficking and increased targeting for degradation. We propose that stalled folding intermediates could define a critical proteostasis pathway branch-point(s) responsible for the loss of function in misfolding diseases as observed in CF