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Background Asthma with neutrophil predominance is challenging to treat with corticosteroids. Novel treatment options for asthma include those that target innate immune activity. Recent literature has indicated a significant role for IL-1β in both acute and chronic neutrophilic asthma. Objective This study used inhaled endotoxin (LPS) challenge as a model of innate immune activation to a) assess the safety of the interleukin-1 receptor antagonist, anakinra, in conjunction with inhaled LPS and b) to test the hypothesis that IL-1 blockade will suppress acute neutrophil response to challenge with inhaled LPS. Methods In a phase I clinical study, 17 healthy volunteers completed a double-blinded, placebo controlled crossover study where they received 2 daily subcutaneous doses of 1 mg/kg anakinra (maximum dose of 100 mg) or saline (placebo). One hour after the second treatment dose, subjects underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 4 hours after inhaled LPS. The effect of anakinra compared to placebo on airway neutrophils and airway pro-inflammatory cytokines after LPS challenge was compared using a linear mixed model approach. Results Anakinra pretreatment significantly diminished airway neutrophilia compared to placebo. LPS-induced IL-1β, IL-6, and IL-8 were significantly reduced during the anakinra treatment period compared to placebo. Subjects tolerated the anakinra treatment well, without increased frequency of infections that were attributable to anakinra treatment. Conclusions Anakinra effectively reduced airway neutrophilic inflammation and resulted in no serious adverse events in a model of inhaled LPS challenge. Anakinra is a potential therapeutic candidate for treatment of asthma with neutrophil predominance in diseased populations.

Rationale Epidemiologic studies suggest that dietary vitamin E is an important candidate intervention for asthma. Our group has shown that daily consumption of vitamin E (gamma tocopherol, γT) has anti-inflammatory actions in both rodent and human phase I studies. The objective of this study was to test whether γT supplementation could mitigate a model of neutrophilic airway inflammation in rats and in healthy human volunteers. Methods F344/N rats were randomized to oral gavage with γT versus placebo, followed by intranasal LPS (20 ug) challenge. Bronchoalveolar lavage fluid and lung histology were used to assess airway neutrophil recruitment. In a phase IIa clinical study, 13 nonasthmatic subjects completed a double-blinded, placebo controlled crossover study where they consumed either a γT-enriched capsule or a sunflower oil placebo capsule. After 7 days of daily supplementation, they underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 6 hours after inhaled LPS. The effect of γT compared to placebo on airway neutrophils post-LPS was compared using a repeated measures analysis of variance. Results In rats, oral γT supplementation significantly reduced tissue infiltration (p<0.05) and accumulation of airway neutrophils (p<0.05) that are elicited by intranasal LPS challenge compared to control rats. In human volunteers, γT treatment significantly decreased induced sputum neutrophils (p=0.03) compared to placebo. Conclusion Oral supplementation with γT reduced airway neutrophil recruitment in both rat and human models of inhaled LPS challenge. These results suggest that γT is a potential therapeutic candidate for prevention or treatment of neutrophilic airway inflammation in diseased populations.

Objective Mucociliary clearance sustains a baseline functionality and an “on demand” capability to upregulate clearance upon irritant exposure involving mucus hypersecretion and accelerated ciliary beat frequency (CBF) modulated by nitric oxide (NO). This study characterized these elements as well as cellular and exogenous NO concentrations subsequent to a single exposure to tobacco smoke (TS) or e-cigarette vapor (EV) on cultured human airway epithelium. Materials and methods Air-liquid interface (ALI) airway epithelial cultures per nonsmoking human subjects were subjected to single TS or EV exposures. Measures of ciliary function and secretion were performed and cellular and exogenous NO concentrations under control and experimental conditions were assessed. Results Both TS and EV exposures resulted similar patterns of decline in CBF within 1 min of the completion of exposure followed by a gradual return often exceeding baseline within 1 h. Post-exposure examination of exposed cultures suggested morphologic differences in secretory function relative to controls. The relative NO concentrations of TS and EV chamber air were sharply different with EV NO being only slightly elevated relative to cellular NO production. Discussion and conclusions Epithelial remodeling and mucociliary dysfunction have been clearly associated with TS exposure. However, information contrasting epithelial structure/function following a single acute TS or EV exposure is limited. This study demonstrates a similar pattern of epithelial response to acute TS or EV exposure. Inasmuch as NO may contribute to an inflammatory milieu and generation of toxic metabolites, it is plausible that recurrent exposures over time may be contributory to chronic pathologies.

A "good death" involving a quality end-of-life experience is the foundational goal overarching all therapy and medicine in the provision of palliative care. Arguably, an occupation-focused approach provided by therapists meets client needs to enable meaningful experiences in the limited time left to them. Current occupational therapy practice environments are not necessarily achieving these goals in commensurate fashion. There is a need to promote the role of occupational therapy and circumscribe what therapists can offer. Further research is necessitated across all environments and future funding for therapist positions in palliative teams. End-of-life care can be complex and challenging; however, therapists can facilitate fulfillment of client-centered occupational goals. In engaging with personally constructed nuances of meaning, quality of life can be improved in those deserving of a significant and emotionally rich daily existence during their final days.