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Persistent airway inflammation, mucus production, and airway hyperreactivity are the major contributors to the frequency and severity of asthma. Why lung inflammation persists in asthmatics remains unclear. It has been proposed that Fas-mediated apoptosis of inflammatory cells is a fundamental mechanism involved in the resolution of eosinophilic airway inflammation. Because infiltrating eosinophils are highly sensitive to Fas-mediated apoptosis, it has been presumed that direct ligation of Fas on eosinophils is involved. Here, we utilize adoptive transfers of T cells to demonstrate that the delayed resolution of eosinophilia in Fas-deficient mice is a downstream effect of Fas deficiency on T cells, not eosinophils. Interestingly, the mice that received Fas-deficient T cells, but not the controls, developed a persistent phase of inflammation that failed to resolve even 6 wk after the last challenge. This persistent phase correlated with decreased interferon (IFN)γ production by Fas-deficient T cells and could be reproduced with adoptive transfer of IFNγ-deficient T cells. These data demonstrate that Fas deficiency on T cells is sufficient for the development of long-term allergic airway disease in mice and implies that deregulation of death receptors such as Fas on human T cells could be an important factor in the development and/or chronic nature of asthma.

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Context Episodic dyspnea is one of the most common, debilitating and difficult-to-treat symptoms. Objective We conducted a pilot study to examine the effect of prophylactic FBT on exercise-induced dyspnea. Methods In this parallel, double-blind randomized placebo-controlled trial, opioid-tolerant patients were asked to complete a 6 minute walk test (6MWT) at baseline, then a second 6MWT 30 minutes after a single dose of FBT (equivalent to 20-50% of their total opioid dose) or matching placebo. We compared dyspnea numeric rating scale (NRS, 0-10, primary outcome), walk distance, vital signs, neurocognitive function and adverse events between the two 6MWTs. Results Among 22 patients enrolled, 20 (91%) completed the study. FBT was associated with a significant within-arm reduction in dyspnea NRS between 0 and 6 minutes (mean change -2.4, 95% confidence interval [CI] -3.5, -1.3) and respiratory rate (mean change -2.6, 95% CI -4.7, -0.4). Placebo was also associated with a non-statistically significant decrease in dyspnea (mean change -1.1). Between arm comparison of dyspnea scores in the second 6MWT favored FBT, albeit not statistically significant (estimate -0.25, P=0.068). Global impression revealed more patients in the FBT group than placebo group reporting their dyspnea was at least “somewhat better” in the second 6MWT (4/9 vs. 0/11, P=0.03). The other secondary outcomes did not differ significantly between arms. Conclusions This study supports that prophylactic FBT was associated with a reduction of exertional dyspnea and was well-tolerated. Our findings support the need for larger trials to confirm the therapeutic potential of rapid-onset opioids.