Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma.

Th2 cytokines and their downstream Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathways play a critical role in allergic asthma. We studied the effects of a pan-JAK inhibitor, pyridone 6 (P6), on asthmatic responses in a mouse model and investigated the mechanism for its biological effects. Mice were sensitized and challenged by ovalbumin (OVA). P6 treatment during the challenge phase suppressed eosinophilia in bronchoalveolar lavage (BAL) fluids but did not affect airway hyperresponsiveness (AHR). To improve the efficacy of the JAK inhibitor, P6 was encapsulated in polylactic-coglycolic acid nanoparticles (P6-PLGA). P6-PLGA treatment just before OVA challenge suppressed both airway eosinophilia and AHR. Although the IL-13 levels in BAL fluids and the OVA-specific IgE levels in serum after the challenge phase treatment with P6-PLGA were similar to those after a sham treatment, the eotaxin levels in BAL fluids and lung mCLCA3/Gob-5 expression were decreased in P6-PLGA-treated mice. Interestingly, the local IL-13 levels and serum OVA-specific IgE were decreased, while IL-17-producing T cells were increased by P6-PLGA treatment during the sensitization plus challenge phases. In vitro, P6 strongly suppressed the differentiation of Th2 from naive CD4 T cells, but it partly enhanced Th17 differentiation. P6 potently suppressed IL-13-mediated STAT6 activation and mCLCA3/Gob-5 expression in mouse tracheal epithelial cells. These findings suggest that the JAK inhibitor P6 suppresses asthmatic responses by inhibiting Th2 inflammation and that application of PLGA nanoparticles improves the therapeutic potency of P6.

Airflow limitation and tongue microbiota in community-dwelling elderly individuals.

Numerous oral indigenous microorganisms are constantly introduced into the stomach via the laryngopharynx, and a portion of these microorganisms irregularly reaches the lower airways and lungs. This study investigated the association between airflow limitation and the status of tongue microbiota, which is a primary source of ingested oral bacterial populations. The study population consisted of 484 community-dwelling adults aged 70-80 years inhabiting Hisayama town, Japan, who underwent a regular health examination including dental examination and spirometry test in 2016. The bacterial density and composition of their tongue microbiota were determined using a previously used 16S rRNA gene to understand their relationship with oral health conditions. The present cross-sectional study compared the tongue microbiota status between elderly individuals with airflow limitation and those with normal airflow. The total bacterial density of the tongue microbiota of individuals with airflow limitation was significantly higher than that of individuals with normal airflow. Logistic regression analysis demonstrated that a high-biomass tongue microbiota was significantly associated with airflow limitation after adjustment for smoking intensity and other covariates (adjusted OR 1.61, 95% CI 1.01-2.60). Of the predominant commensals, higher amounts of Prevotella melaninogenica and Actinomyces odontolyticus were associated with a higher prevalence of airflow limitation. These results indicate that increased bacterial burden in the tongue microbiota is associated with a higher prevalence of airflow limitation.

Periodontal status and lung function decline in the community: the Hisayama study.

This study aimed to determine whether periodontal status is related to a decline in lung function in a general Japanese population. We followed a total of 1,650 community-dwelling individuals (≥40 years) without chronic obstructive pulmonary disease, with at least one teeth, for 3 years. Periodontal status was assessed at baseline by clinical attachment loss (CAL) and probing pocket depth (PPD) at two sites for each tooth, and the mean values were calculated for each subject. Lung function was measured at baseline and follow-up using spirometry, and longitudinal decline in forced expiratory volume in one second (FEV1) was calculated. Multivariate Poisson regression with robust error variance was used to estimate risk ratio (RR). After adjusting for potential confounders including smoking status, there was a tendency for the adjusted RR of developing rapid lung function decline (≥160 mL/3years, the highest quartile of the distribution of FEV1 declines) to increase as mean CAL levels increased (P trend = 0.039). Likewise, a positive association was observed between mean PPD levels and RR of developing rapid lung function decline (P trend = 0.047). Our findings suggest deterioration of periodontal status could be a risk factor for rapid lung function decline in the general Japanese population.