John L. Faul

Interleukin-17–producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity

Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1−/− mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a−/− or Nlrp3−/− mice. AHR was also associated with the expansion of CCR6+ type 3 innate lymphoid cells (ILCs) producing IL-17A (ILC3 cells) in the lung, which could by themselves mediate AHR when adoptively transferred into Rag2−/−; Il2rg−/− mice treated with recombinant IL-1β. Macrophage-derived IL-1β production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1β with an IL-1 receptor antagonist abolished obesity-induced AHR and reduced the number of ILC3 cells. As we found ILC3-like cells in the bronchoalveolar lavage fluid of individuals with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3 cells.

Simvastatin Rescues Rats From Fatal Pulmonary Hypertension by Inducing Apoptosis of Neointimal Smooth Muscle Cells

Background—Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. Methods and Results—Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]=42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg · kg−1 · d−1 by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP=36 mm Hg) and 6 weeks (mPAP=24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-&agr; and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. Conclusions—Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury.

Lung immunopathology in cases of sudden asthma death

The histopathology of airway inflammation in rare cases of sudden asphyxic asthma death (SAAD) is unclear. This study examines, for the first time, the relative disposition of lymphocyte and macrophage subsets and eosinophils in proximal and distal tissues of such cases. Multiple resection specimens from five cases of SAAD were studied. Tissue blocks were obtained at necroscopy and immediately frozen in liquid nitrogen within 18 hours of death (death occurring within 1 h of the onset of an unprovoked asphyxic asthma attack). After immunohistological staining, frozen sections underwent semi-quantitative analysis (cell counts per unit area) for T-cells, macrophages and eosinophils using computerized imaging systems. Subsets of T-cells and macrophages were estimated using double immunofluorescence techniques. Variability within samples, between samples and between cases was compared. These cases of fatal asthma showed infiltrates of T-cells, macrophages and eosinophils within peribronchial tissues. Distinct from stable asthma, a CD8+ T-cell dominance was found. A high proportion of eosinophils were activated (EG2+), whereas the relative proportion of antigen-presenting cells (RFD1+) did not seem to be abnormal, although numbers of these cells were high. These features were seen both in proximal and distal tissues. The variability of these parameters within an individual was 9.4-15.2%, however, the variability between individual cases was greater. Sudden asphyxic asthma is associated with inflammatory infiltrates both of proximal and distal lung tissues. In contrast to stable asthma, this infiltrate contains large numbers of CD8+ T-cells, suggesting distinct qualitative as well as quantitative characteristics in the immunopathology of sudden asthma death.

Natural killer T cells in the lungs of patients with asthma.

1 Division of Immunology and Allergy, Department of Pediatrics, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA 2 Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 3 Respiratory Department, Connolly Hospital Blanchardstown, Dublin, Ireland 4 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA 5 Diabetes Unit, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA 6 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Allergen-induced CD30 expression on T cells of atopic asthmatics

Background The importance of TH2‐type T cell cytokines in atopic disease is widely accepted. CD30, a member of the TNF/NGF receptor superfamily, is expressed on a proportion of activated CD45RO+ T cells and has been proposed as a marker for TH2 phenotype. CD30 ligand‐CD30 interaction has been shown to positively influence development of the TH2 phenotype, and serum levels of soluble CD30 (sCD30) have been used as prognostic markers in HIV, SLE, Epstein‐Barr Virus infection and Hodgkins Lymphoma but not as yet in allergic disease.

Dietary nitrate supplementation in COPD: An acute, double-blind, randomized, placebo-controlled, crossover trial.

BACKGROUND The acute consumption of dietary nitrate has been shown to improve exercise capacity in athletes, healthy adults and subjects with peripheral vascular disease. Many COPD patients have reduced exercise capacity. We hypothesized that acute nitrate consumption might increase incremental shuttle walk test (ISWT) distance in COPD subjects. METHODS Eleven COPD subjects were randomly assigned to consume either a high nitrate or a matched, low nitrate beverage in a double-blind, randomized, placebo-controlled, crossover design. ISWT distance was measured both before and 3 h after the beverage and change was recorded. After a 7-day washout, ISWT distances were re-measured before and 3 h after the alternate beverage and changes were recorded. RESULTS We observed an increase in ISWT distance after consuming the high nitrate juice (25 m) compared with a reduction after the low nitrate juice (14 m) (p < 0.01). This improvement in exercise capacity was associated with significant increases in serum nitrate (p < 0.000005) and nitrite (p < 0.01) levels and a significant lowering of resting blood pressure (<0.05). CONCLUSIONS In patients with stable COPD, the acute consumption of dietary nitrate increased serum nitrate/nitrite levels and exercise capacity and was associated with a decrease in resting blood pressure. Nitrate consumption might alter exercise capacity in COPD patients.

T-cell cytokines may control the balance of functionally distinct macrophage populations.

As monocytes differentiate into mature macrophages, subsets emerge that exhibit stimulatory, suppressive or phagocytic potential. These functionally distinct subsets can be discriminated using monoclonal antibodies RFD1 and RFD7. As examples of all these subsets have been repeatedly identified within the macrophage pool in a variety of organs the overall functional capacity of this pool will depend on the relative balance of these subpopulations. This study investigates whether this balance present in mature macrophage populations can be regulated by the local influence of T‐cell‐derived cytokines. The dose‐dependent effect of cytokines interferon‐γ (IFN‐γ), interleukins (IL) IL‐2, IL‐4 and IL‐10 on the phenotype and function of monocyte‐derived macrophages was determined. Subsets of mature cells were quantified by identifying RFD1+ RFD7− stimulatory cells (D1+); RFD1− RFD7+ phagocytes (D7+) and RFD1+ RFD7+ suppressive cells (D1/D7+). IFN‐γ and IL‐4 increased the relative proportions of D1+ stimulatory cells and upregulated HLA‐DR expression. IFN‐γ also increased the capacity of the mature macrophage pool to stimulate T‐cell proliferation. IL‐10 reduced the proportions of D1+ stimulatory cells while promoting the differentiation of D7+ phagocytes and D1/D7+ suppressive cells. IL‐10 induced changes also reduced the functional capacity of the mature populations to stimulate T cells in auto and allogenic mixed lymphocyte reactions (MLR). IL‐2 had no effect on differentiation of monocytes. Thus IL‐4 and IFN‐γ are seen to induce the development of stimulatory macrophages while IL‐10 promotes differentiation of monocytes to mature phagocytes and suppressive macrophages. It is concluded that mature macrophage phenotype is ‘plastic’ and under the control of T‐cell‐derived mediators. Furthermore, within the differentiating monocytes, phenotypic change appears to carry with it functional change, thus retaining the relationship between antigen expression and activity in the mature macrophage populations.

The Effect of an Inhaled Corticosteroid on Glucose Control in Type 2 Diabetes

Objective: To determine the effect of inhaled corticosteroid (ICS) therapy on glucose control in adults with type 2 diabetes mellitus and coexisting asthma or chronic obstructive pulmonary disease (COPD). Design: A prospective randomized, double-blind, double-dummy placebo-controlled, crossover investigation of inhaled steroids and oral leukotriene blockers. Setting: A United States Department of Veterans Affairs Health Care System outpatient setting. Participants: Adults with type 2 diabetes and asthma or COPD. Methods: Subjects (n=12) were randomized to receive either inhaled fluticasone propionate (440 μg twice daily) and oral placebo, or inhaled placebo and oral montelukast (10 mg/day). After 6 weeks, subjects were switched to the opposite therapy for 6 weeks. The primary outcome measure was the change in the percentage of glycosylated hemoglobin (%HbA1c) at 6 weeks relative to the baseline value. Results: Ten patients completed the study. The difference between the mean within-subject changes in %HbA1c associated with 6-week periods of fluticasone and the mean changes associated with montelukast therapy was small but statistically significant (mean difference=0.25; P<0.025). Neither fluticasone nor oral montelukast therapy for 6 weeks led to a significantly different mean % HbA1c compared with the relevant baseline (mean differences=0.11 and −0.14, respectively). Conclusion: The absence of a clinically significant within-subject difference in the changes in %HbA1c associated with fluticasone versus oral montelukast therapy, or between either therapy or baseline does not warrant recommending changes in therapy for asthma or diabetes in patients with these co-morbid conditions. However, we suggest that clinicians carefully monitor blood glucose control when diabetic patients initiate ICS, especially with higher dosages.

Fluticasone propionate induced alterations to lung function and the immunopathology of asthma over time

BACKGROUND Inhaled corticosteroids are the most widely used treatment for asthma, a disease characterised by both functional and immunopathological abnormalities. This study investigated the relative effects of inhaled corticosteroids on these two features of asthma over time. METHODS A randomised, double blind, placebo controlled, parallel group study with inhaled fluticasone propionate, (FP 2 mg daily) was conducted in 27 patients with asthma. Following baseline analysis, the study tested the effects of short term (two weeks) and longer term (eight weeks) treatment. At each time point (0, 2, and 8 weeks) lung function tests were performed and endobronchial biopsy specimens obtained to determine the distribution and number of lymphocyte, macrophage and eosinophil subsets using immunohistological analysis. Twenty three patients completed the study, 11 on FP and 12 placebo. RESULTS FEV1, ΔFEV1, FEF25–75, and FEV1/FVC all improved after two weeks of FP treatment. This improvement was maintained but not increased after eight weeks. PC20FEV1 showed a trend to increase but was not significantly improved at eight weeks. No significant changes were seen in the placebo group. The numbers of T cells, macrophages, and eosinophils in the bronchial wall were reduced by two weeks of treatment with FP but were unaltered by placebo. The improvement offered by FP continued over the eight week period. Reductions in CD4:CD8 ratio and numbers of activated (EG2+) eosinophils were only significant after eight weeks of treatment. CONCLUSIONS These results reveal that FP influences both functional and immunopathological parameters of asthma. Temporal relationships suggest that these are parallel but not necessarily interrelated effects. While short term treatment is effective in “normalising” the functional abnormalities in asthma, the impact of FP on bronchial inflammation appears to be progressive, taking up to eight weeks and more.

Creation of an iliac arteriovenous shunt lowers blood pressure in chronic obstructive pulmonary disease patients with hypertension.

OBJECTIVE Vasodilators are used with caution in patients with chronic obstructive pulmonary disease (COPD). We have developed a device for percutaneous arteriovenous shunt creation in the iliac region to increase cardiac output and oxygen delivery for patients with COPD. Although this device does not cause significant blood pressure changes in normotensive patients with COPD, we hypothesized that arteriovenous shunt creation might cause vasodilator effects in hypertensive patients because of a reduction in vascular resistance. METHODS Twenty-four patients with COPD and hypertension enrolled in an open label study of arteriovenous shunt creation for COPD. We performed cardiac catheterization at baseline and again 3 to 6 months after the procedure. As a safety measure we also recorded office blood pressure at baseline and again after 3, 6, 9, and 12 months. RESULTS The procedure increased oxygen delivery (1.1-1.4 L.min(-1)) and cardiac output (6-8.2 L.min(-1)) (P < .001) and lowered both the systemic vascular resistance (P < .001) and the pulmonary vascular resistance (P < .01). After 12 months, however, the average systolic blood pressure was reduced from 145 to 132 mm Hg (P < .0001), and the average diastolic blood pressure was reduced from 86 to 67 mm Hg (P < .0001). CONCLUSIONS Percutaneous iliac arteriovenous fistula creation for COPD causes a significant and persistent lowering of blood pressure in patients with co-existing hypertension.