Post-allergen challenge inhibition of poly(ADP-ribose) polymerase harbors therapeutic potential for treatment of allergic airway inflammation.

BACKGROUND: Identifying therapeutic drugs that block the release or effects of T-helper type 2 (Th2) cytokines after allergen exposure is an important goal for the treatment of allergic inflammatory diseases including asthma. We recently showed, using a murine model of allergic airway inflammation, that poly(ADP-ribose) polymerase (PARP) plays an important role in the pathogenesis of asthma-related lung inflammation. PARP inhibition, by single injection of a novel inhibitor, thieno[2,3-c]isoquinolin-5-one (TIQ-A), before ovalbumin (OVA) challenge, prevented airway eosinophilia in C57BL/6 mice with concomitant suppression of Th2 cytokine production and mucus secretion. OBJECTIVE: To evaluate the efficacy of the drug when it is given after OVA challenge for its possible therapeutic potential. METHODS: This study was conducted using a murine model of allergic airway inflammation. RESULTS: A single injection of TIQ-A (6 mg/kg) one or 6 h post-allergen challenge conferred similar reduction in OVA challenge-induced eosinophilia. More significantly, post-allergen challenge administration of the drug exerted even better suppression on the production of IL-4, IL-5, IL-13, and IgE and prevented airway hyperresponsiveness to inhaled-methacholine. The significant decrease in IL-13 was accompanied by a complete absence of airways mucus production indicating a potential protection against allergen-induced airway remodelling. CONCLUSION: The coincidence of the inflammation trigger and the time of drug administration appear to be important for the drug's more pronounced protection. The observed time window for efficacy, 1 or 6 h after allergen challenge may be of great clinical interest. These findings may provide a novel therapeutic strategy for the treatment of allergic airway inflammation, including asthma.

Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression.

Elevated levels of combustion-derived particulate matter (CDPM) are a risk factor for the development of lung diseases such as asthma. Studies have shown that CDPM exacerbates asthma, inducing acute lung dysfunction and inflammation; however, the impact of CDPM exposure on early immunological responses to allergens remains unclear. To determine the effects of early-life CDPM exposure on allergic asthma development in infants, we exposed infant mice to CDPM and then induced a mouse model of asthma using house dust mite (HDM) allergen. Mice exposed to CDPM+HDM failed to develop a typical asthma phenotype including airway hyper-responsiveness, T-helper type 2 (Th2) inflammation, Muc5ac expression, eosinophilia, and HDM-specific immunoglobulin (Ig) compared with HDM-exposed mice. Although HDM-specific IgE was attenuated, total IgE was twofold higher in CDPM+HDM mice compared with HDM mice. We further demonstrate that CDPM exposure during early life induced an immunosuppressive environment in the lung, concurrent with increases in tolerogenic dendritic cells and regulatory T cells, resulting in the suppression of Th2 responses. Despite having early immunosuppression, these mice develop severe allergic inflammation when challenged with allergen as adults. These findings demonstrate a mechanism whereby CDPM exposure modulates adaptive immunity, inducing specific antigen tolerance while amplifying total IgE, and leading to a predisposition to develop asthma upon rechallenge later in life.

Mouse eosinophil-associated ribonucleases: a unique subfamily expressed during hematopoiesis.

A unique family of ribonucleases was identified by exhaustive screening of genomic and cDNA libraries using a probe derived from a gene encoding a ribonuclease stored in the mouse eosinophil secondary granule. This family contains at least 13 genes, which encode ribonucleases, and two potential pseudogenes. The conserved sequence identity among these genes (approximately 70%), as well as the isolation/purification of these ribonucleases from eosinophil secondary granules, has led us to conclude that these genes form a unique clade in the mouse that we have identified as the Ear (Eosinophil-associated ribonuclease) gene family. Analyses of the nucleotide substitutions that have occurred among these ribonuclease genes reveal that duplication events within this family have been episodic, occurring within three unique periods during the past 18 x 10(6) years. Moreover, comparisons of non-synonymous (K(a)) vs. synonymous (K(s)) rates of nucleotide substitution show that although these genes conserve residues necessary for RNase activity, selective evolutionary pressure(s) exist such that acquired amino acid changes appear to be advantageous. The selective advantage of these amino acid changes is currently unclear, but the occurrence of this phenomenon in both the mouse and the human highlights the importance of these changes for Ear and, therefore, eosinophil effector function(s).

Extensive eosinophil degranulation and peroxidase-mediated oxidation of airway proteins do not occur in a mouse ovalbumin-challenge model of pulmonary inflammation.

Paradigms of eosinophil effector function in the lungs of asthma patients invariably depend on activities mediated by cationic proteins released from secondary granules during a process collectively referred to as degranulation. In this study, we generated knockout mice deficient for eosinophil peroxidase (EPO) to assess the role(s) of this abundant secondary granule protein in an OVA-challenge model. The loss of EPO had no effect on the development of OVA-induced pathologies in the mouse. The absence of phenotypic consequences in these knockout animals extended beyond pulmonary histopathologies and airway changes, as EPO-deficient animals also displayed OVA-induced airway hyperresponsiveness after provocation with methacholine. In addition, EPO-mediated oxidative damage of proteins (e.g., bromination of tyrosine residues) recovered in bronchoalveolar lavage from OVA-treated wild-type mice was <10% of the levels observed in bronchoalveolar lavage recovered from asthma patients. These data demonstrate that EPO activities are inconsequential to the development of allergic pulmonary pathologies in the mouse and suggest that degranulation of eosinophils recruited to the lung in this model does not occur at levels comparable to those observed in humans with asthma.