The role of intrinsic efficacy in determining response to a β2-agonist in acute severe asthma

SummaryBackgroundCurrent guidelines recommend repeated doses of albuterol for the emergency treatment of acute asthma. However, approximately one-third of patients show little or no initial response to this partial β2-agonist.MethodsWe conducted a randomized, double-blind, proof-of-concept study to investigate whether a full β2-agonist, isoproterenol, offers a therapeutic advantage in adults presenting with acute severe asthma (FEV1<50%) who fail to respond to an initial treatment of the partial β2-agonist, albuterol. Study subjects were randomized to receive a 2-h continuous nebulization of either albuterol (7.5mg/h) (n=10, mean FEV1=37% predicted) or isoproterenol (7.5mg/h) (n=9, mean FEV1=33% predicted). Respiratory symptoms, vital signs and pulmonary function measures were collected.ResultsSubjects from both treatment groups had similar baseline characteristics. The percent improvements from baseline FEV1 at 60 and 120min were significantly higher in subjects receiving isoproterenol than those receiving albuterol (44 vs. 17% and 63 vs. 24%, respectively, P<0.05). The change in symptoms measured by the modified Borg score was also significantly greater in subjects receiving isoproterenol (P<0.01). Both treatments were well tolerated, though the mean increase in pulse rate at 60 and 120min (21 vs. 1 and 23 vs. 6beats/min, respectively, P<0.05) and the mean change in serum potassium at 120min (−0.52 vs. −0.07meq/L, P<0.05) from baseline were significantly greater in the isoproterenol group.ConclusionsOur data suggest that in subjects presenting with acute severe asthma who fail to show an initial response to albuterol, the use of a β2-agonist of higher intrinsic efficacy can be more effective in improving lung function and symptoms

An Immune Basis for Lung Parenchymal Destruction in Chronic Obstructive Pulmonary Disease and Emphysema

BACKGROUND: Chronic obstructive pulmonary disease and emphysema are a frequent result of long-term smoking, but the exact mechanisms, specifically which types of cells are associated with the lung destruction, are unclear. METHODS AND FINDINGS: We studied different subsets of lymphocytes taken from portions of human lungs removed surgically to find out which lymphocytes were the most frequent, which cell-surface markers these lymphocytes expressed, and whether the lymphocytes secreted any specific factors that could be associated with disease. We found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a high percentage of CD4(+) and CD8(+) T lymphocytes that expressed chemokine receptors CCR5 and CXCR3 (both markers of T helper 1 cells), but not CCR3 or CCR4 (markers of T helper 2 cells). Lung lymphocytes in patients with chronic obstructive pulmonary disease and emphysema secrete more interferon gamma—often associated with T helper 1 cells—and interferon-inducible protein 10 and monokine induced by interferon, both of which bind to CXCR3 and are involved in attracting T helper 1 cells. In response to interferon-inducible protein 10 and monokine induced by interferon, but not interferon gamma, lung macrophages secreted macrophage metalloelastase (matrix metalloproteinase-12), a potent elastin-degrading enzyme that causes tissue destruction and which has been linked to emphysema. CONCLUSIONS: These data suggest that Th1 lymphoctytes in the lungs of people with smoking-related damage drive progression of emphysema through CXCR3 ligands, interferon-inducible protein 10, and monokine induced by interferon

Long-term results of the DelIVery for Pulmonary Arterial Hypertension trial

Background: The DelIVery for Pulmonary Arterial Hypertension clinical trial was a multi-center, prospective, single arm, Investigational Device Exemption study utilizing a fully implantable, programmable intravascular delivery system consisting of a pump and a catheter for intravenous treprostinil. The study met its primary endpoint and demonstrated that the intravascular delivery system significantly reduced catheter related complications at 22,000 subject-days of follow-up compared with a predefined objective performance criterion. Here we summarize the results obtained during a 6.4-year follow-up period. Methods: Throughout study follow-up, participants had clinic visits and medication refills at least every 12 weeks (dependent on the subjects\u27 dose). All adverse events and intravascular delivery system complications were evaluated and recorded. Results: Sixty pulmonary arterial hypertension subjects were followed post device implantation for approximately 282 patient-years (range 87 days to 6.4 years). Of the 60 subjects, 14 died (1 related to intravascular delivery system pump failure), 2 withdrew after lung transplants, and 2 withdrew due to pump pocket infection. No catheter-related bloodstream infections, catheter thrombosis or occlusions, or catheter kinks occurred through 282 patient-years. Two participants had adverse events of abdominal pain, rash, due to subcutaneous treprostinil leaks after one catheter puncture and one catheter laceration during pump refill and replacement, respectively. Eight pump failure events occurred: seven pump motor stalls and one early replacement (faulty battery). Conclusion: Delivery of treprostinil with an intravascular delivery system is a safe alternative to an external delivery system, while providing enhanced life experiences. To preserve the risk-benefit ratio, treatment at specialized pulmonary arterial hypertension centers is recommended until training is disseminated at other sites

Chemokine Receptor Expression on Peripheral Lung Lymphocytes

<div><p>(A) Single color histograms showing expression of chemokine receptors CCR4, CCR5, and CXCR3 from representative control and emphysema participants.</p> <p>(B) Pooled data from all participants (control, <i>n =</i> 10; emphysema, <i>n =</i> 18) showing percent (median ± SD) of total lung lymphocytes expressing CCR4 and CCR5.</p> <p>(C) Pooled data from same participants showing percent (median ± SD) CCR5 expression on CD4 (top) and CD8 (middle) T cells, and CXCR3 expression on unfractionated T cells (bottom) from the same participant groups.</p> <p>(D) Analysis of total lung lymphocyte chemokine receptor (median ± SD) profiles among participants with emphysema. Participants had either (1) lung volume reduction surgery for emphysema (non-cancer, <i>n =</i> 8) or (2) lung resection for treatment of small peripheral cancer (<i>n =</i> 10). Participants showed similar inflammatory indices as determined by CCR5 expression.</p> <p>In (B) and (C), *, <i>p</i> < 0.001; †, <i>p =</i> 0.01; ‡, <i>p =</i> 0.02; ∫, <i>p =</i> 0.007 (Mann-Whitney test) for the comparison of emphysema and control groups.</p></div

IFN-γ, MIG, and IP-10 Production by Isolated Lung Lymphocytes

<div><p>(A–C) Lung lymphocytes from control individuals and participants with emphysema were cultured without additional stimulation for 3 or 4 d and assessed for secretion of (A) IFN-γ, (B) MIG, and (C) IP-10 (control, <i>n =</i> 8; emphysema, <i>n =</i> 12). Columns are median, bars represent SD. *, <i>p=</i> 0.007; †, <i>p =</i> 0.01; ‡, <i>p =</i> 0.02 for the comparison of emphysema and control participants.</p> <p>(D) The same cells from a representative ex-smoker individual with emphysema were either left unstimulated (No ST) or treated with PMA/ionomycin (PMA/I) for 24 h and assessed for surface CD8 and CD69 expression and the intracytoplasmic accumulation of IFN-γ by flow cytometry.</p> <p>(E) Production of IL-4 by lung lymphocytes. Lung lymphocytes from a representative ex-smoker individual with emphysema were cultured for 24 h with or without PMA/ionomycin stimulation (PMA/I) and assessed for intracytoplasmic IL-4 and IFN-γ accumulation by flow cytometry.</p></div

Expression of CXCR3 in Lungs of Control and Emphysematous Smoker Individuals

<div><p>(A) Representative forward and side-scatter characteristics of whole lung cells from a participant with COPD and emphysema. Anti-CD11b PE-conjugated and anti-CD14 FITC-conjugated antibodies detect lung macrophages (middle), and histogram of mean fluorescence intensity showing anti-CXCR3-Cy5 and control antibodies (cIg) detects lung macrophages in the patient with emphysema.</p> <p>(B) Pooled data from control individuals without (<i>n =</i> 5) and with (<i>n =</i> 8) emphysema. Columns are median, bars represent SD. *, <i>p =</i> 0.009 (Mann-Whitney test) for the comparison of emphysema and control participants.</p> <p>(C) Negative association between CXCR3 expression on CD3⁺ T cells and FEV1 percentage predicted based on an <i>R²</i> goodness-of-fit statistic of 0.27 (<i>p =</i> 0.0089, <i>r</i> = −0.52, <i>n =</i> 24).</p></div

Regulation of MMP12 by Type 1 Cytokines

<div><p>(A) CD14⁺, lymphocyte-depleted lung leukocytes were cultured with and without the indicated amounts of recombinant human IP-10 and IFN-γ, and supernatants were assessed for the presence of MMP12 by Western blotting.</p> <p>(B) Fold increase relative to unstimulated of MMP12 mRNA from lung macrophages stimulated without (<b>–</b>) and with (<b>+</b>) 500 ng/ml of IP-10 in the presence or absence of a function-blocking antibody to CXCR3 as determined by real-time PCR.</p> <p>(C and D) Lung tissue from a participant with emphysema (C) shows strong immune staining for MMP12 localized to macrophages (arrows), and (D) shows lung tissue from a control participant without emphysema and with undetectable MMP12. The insets show a high-power view of lung macrophages staining positive (C) and negative (D) for MMP12 (×60) *, <i>p =</i> 0.04.</p></div