Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by neutrophil-driven lung destruction and early emphysema in a low AAT, and high neutrophil elastase environment in the lungs of affected individuals. In this study, we examined peripheral blood neutrophil apoptosis and showed it to be accelerated in individuals with AATD by a mechanism involving endoplasmic reticulum stress and aberrant TNF-α signaling. We reveal that neutrophil apoptosis in individuals homozygous for the Z allele (PiZZ) is increased nearly 2-fold compared with healthy controls and is associated with activation of the external death pathway. We demonstrate that in AATD, misfolded AAT protein accumulates in the endoplasmic reticulum of neutrophils, leading to endoplasmic reticulum stress and the expression of proapoptotic signals, including TNF-α, resulting in increased apoptosis and defective bacterial killing. In addition, treatment of AATD individuals with AAT augmentation therapy decreased neutrophil ADAM-17 activity and apoptosis in vivo and increased bacterial killing by treated cells. In summary, this study demonstrates that AAT can regulate neutrophil apoptosis by a previously unidentified and novel mechanism and highlights the role of AAT augmentation therapy in ameliorating inflammation in AATD.

Leukotriene B4 (LTB4) contributes to many inflammatory diseases, including genetic and nongenetic forms of chronic obstructive pulmonary disease. α-1 Antitrypsin (AAT) deficiency (AATD) is characterized by destruction of lung parenchyma and development of emphysema, caused by low AAT levels and a high neutrophil burden in the airways of affected individuals. In this study we assessed whether AATD is an LTB4-related disease and investigated the ability of serum AAT to control LTB4 signaling in neutrophils. In vitro studies demonstrate that neutrophil elastase is a key player in the LTB4 inflammatory cycle in AATD, causing increased LTB4 production, and associated BLT1 membrane receptor expression. AATD patients homozygous for the Z allele were characterized by increased neutrophil adhesion and degranulation responses to LTB4. We demonstrate that AAT can bind LTB4 and that AAT/LTB4 complex formation modulates BLT1 engagement and downstream signaling events, including 1,4,5-triphosphate production and Ca2+ flux. Additionally, treatment of ZZ-AATD individuals with AAT augmentation therapy decreased plasma LTB4 concentrations and reduced levels of membrane-bound neutrophil elastase. Collectively, these results provide a mechanism by which AAT augmentation therapy impacts on LTB4 signaling in vivo, and not only reinforces the utility of this therapy for resolving inflammation in AATD, but supports useful future clinical applications in treatment of other LTB4-related diseases.

Figure 1). This injurious inflation pattern is known to cause overstretch and tidal recruitment in dependent, atelectatic lung, and thereby worsen dependent lung injury (7-9). Reverse triggering increased dependent lung stretch equivalent to that applied by VT of up to 15 ml/kg during muscle paralysis, despite a constant VT (Figure 2). Second, the magnitude of negative swing in Pes during reverse triggering is proportional to the local lung stretch in dependent lung, reflecting greater propensity to injury. Monitoring Pes or electrical activity of diaphragm could contribute in two ways. Each of these modalities increases the recognition of reverse triggering, and they quantify the magnitude of inspiratory muscle force during reverse triggering. Although reverse triggering associated with breath stacking is readily detected, in the absence of breath stacking it is likely to be unnoticed by clinicians relying on standard waveforms (e.g., airway pressure and flow). In addition, it will be underestimated when VT is controlled (4). Reverse triggering occurs in deeply sedated patients, a scenario in which clinicians consider the risk for asynchrony to be minimal (4), in contrast to easily detected vigorous effort, which is widely recognized to be harmful (2, 10). Thus, sedation may reduce harm from vigorous effort but increase the incidence of subtle and unsuspected reverse triggering. Finally, estimation of inspiratory muscle force during reverse triggering may be important to decrease dependent lung stretch and potentially lessen injury. It is uncertain whether the inflation pattern associated with reverse triggering is also observed with other ventilator modes. In conclusion, during reverse triggering, injurious inflation occurred in dependent lung despite the constant overall VT, and dependent lung stretch was proportional to the negative deflection in Pes. Early recognition of reverse triggering may be beneficial. n Author disclosures are available with the text of this letter at www.atsjournals.org.

Alpha-1 antitrypsin (AAT) is an acute phase protein that possesses immune regulatory and anti-inflammatory functions independent of anti-protease activity. AAT deficiency (AATD) is associated with early onset emphysema and chronic obstructive pulmonary disease. Of interest are the AATD nonsense mutations (termed Null or Q0) the majority of which arise from premature termination codons (PTC) in the messenger RNA coding-region. We have recently demonstrated that plasma from an AATD patient homozygous for the Null Bolton-allele (Q0bolton) contains AAT protein of truncated size. Although the potential to alleviate the phenotypic consequences of AATD by increasing levels of truncated protein holds therapeutic promise, protein functionality is key. The goal of this study was to evaluate the structural features and anti-inflammatory capacity of Q0bolton-AAT. A low abundance, truncated AAT protein was confirmed in plasma of a Q0bolton- AATD patient and was secreted by patient-derived iPSC-hepatic cells. Functional assays confirmed the ability of purified Q0bolton-AAT protein to bind neutrophil-elastase and to inhibit protease activity. Q0bolton-AAT bound interleukin-8 and leukotriene B4, comparable to control M-AAT, and significantly decreased leukotriene B4 induced neutrophil adhesion (P=0.04). Through a mechanism involving increased mRNA stability (P=0.007), ataluren treatment of HEK-293 significantly increased Q0bolton-AAT mRNA expression (P=0.03) and Q0bolton-AAT truncated protein secretion (P=0.04). Results support the rationale for treatment with pharmacological agents that augment levels of functional Q0bolton-AAT protein, thus offering a potential therapeutic option for AATD patients with rare mutations of similar theratype.

BackgroundOutcomes for patients with chronic obstructive pulmonary disease (COPD) with persistent hypercapnic respiratory failure are improved by long-term home non-invasive ventilation (NIV). Provision of home-NIV presents clinical and service challenges. The aim of this study was to evaluate outcomes of home-NIV in hypercapnic patients with COPD who had been set-up at our centre using remote-monitoring and iVAPS-autoEPAP NIV mode (Lumis device, ResMed).MethodsRetrospective analysis of a data set of 46 patients with COPD who commenced remote-monitored home-NIV (AirView, ResMed) between February 2017 and January 2018. Events including time to readmission or death at 12 months were compared with a retrospectively identified cohort of 27 patients with hypercapnic COPD who had not been referred for consideration of home-NIV.ResultsThe median time to readmission or death was significantly prolonged in patients who commenced home-NIV (median 160 days, 95% CI 69.38 to 250.63) versus the comparison cohort (66 days, 95% CI 21.9 to 110.1; p<0.01). Average time to hospital readmission was 221 days (95% CI, 47.77 to 394.23) and 70 days (95% CI, 55.31 to 84.69; p<0.05), respectively. Median decrease in bicarbonate level of 4.9 mmol/L (p<0.0151) and daytime partial pressure of carbon dioxide 2.2 kPa (p<0.032) in home-NIV patients with no required increase in nurse home visits is compatible with effectiveness of this service model. Median reduction of 14 occupied bed days per annum was observed per patient who continued home-NIV throughout the study period (N=32).ConclusionThese findings demonstrate the feasibility and provide initial utility data for a technology-assisted service model for the provision of home-NIV therapy for patients with COPD.

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Background Outcomes for chronic obstructive pulmonary disease (COPD) patients with persistent hypercapnic respiratory failure are improved by long-term home non-invasive ventilation (NIV). Provision of home-NIV presents clinical and service challenges. The aim of this study was to assess outcomes of home-NIV in hypercapnic COPD patients managed remotely. Methods Retrospective analysis of a dataset of 46 COPD patients with persistent hypercapnic respiratory failure who commenced home-NIV managed by two-way remote monitoring (Lumis, AirView, ResMed) between February 2017 and January 2018. The primary outcome of this study was time to readmission or death at 12 months in patients receiving home-NIV versus a retrospectively identified control cohort of 27 patients with hypercapnic COPD who had not been referred for home-NIV. Results The median time to readmission or death was significantly prolonged in patients who commenced home-NIV (median 160 days, 95% CI 69.38-250.63) versus the control cohort (66 days, 95% CI 21.9-110.1; p<0.01). Average time to hospital readmission was 221 days (95% CI, 47.77-394.23) and 70 days (95% CI, 55.31-84.69; p<0.05), respectively. Median decrease in bicarbonate level of 4.9mmol/L (p<0.0151) and daytime PCO2 2.2kPa (p<0.032) demonstrate efficacy of home-NIV. A median reduction of 14 occupied bed days per annum versus previous year prior to NIV was observed per patient who continued home-NIV throughout the study period (N=32). Conclusion These findings confirm the benefits of home-NIV in clinical practice and support the use of two-way remote monitoring as a feasible solution to managing the delivery of home-NIV for COPD patients with persistent hypercapnia.

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