Joseph Huh

Antielastin autoimmunity in tobacco smoking–induced emphysema

Chronic obstructive pulmonary disease and emphysema are common destructive inflammatory diseases that are leading causes of death worldwide. Here we show that emphysema is an autoimmune disease characterized by the presence of antielastin antibody and T-helper type 1 (TH1) responses, which correlate with emphysema severity. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers.

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

ABSTRACT 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.

Radial Artery Grafts vs Saphenous Vein Grafts in Coronary Artery Bypass Surgery: A Randomized Trial

CONTEXT Arterial grafts are thought to be better conduits than saphenous vein grafts for coronary artery bypass grafting (CABG) based on experience with using the left internal mammary artery to bypass the left anterior descending coronary artery. The efficacy of the radial artery graft is less clear. OBJECTIVE To compare 1-year angiographic patency of radial artery grafts vs saphenous vein grafts in patients undergoing elective CABG. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized controlled trial conducted from February 2003 to February 2009 at 11 Veterans Affairs medical centers among 757 participants (99% men) undergoing first-time elective CABG. INTERVENTIONS The left internal mammary artery was used to preferentially graft the left anterior descending coronary artery whenever possible; the best remaining recipient vessel was randomized to radial artery vs saphenous vein graft. MAIN OUTCOME MEASURES The primary end point was angiographic graft patency at 1 year after CABG. Secondary end points included angiographic graft patency at 1 week after CABG, myocardial infarction, stroke, repeat revascularization, and death. RESULTS Analysis included 733 patients (366 in the radial artery group, 367 in the saphenous vein group). There was no significant difference in study graft patency at 1 year after CABG (radial artery, 238/266; 89%; 95% confidence interval [CI], 86%-93%; saphenous vein, 239/269; 89%; 95% CI, 85%-93%; adjusted OR, 0.99; 95% CI, 0.56-1.74; P = .98). There were no significant differences in the secondary end points. CONCLUSION Among Veterans Affairs patients undergoing first-time elective CABG, the use of a radial artery graft compared with saphenous vein graft did not result in greater 1-year patency. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00054847.

Lung Myeloid Dendritic Cells Coordinately Induce T H 1 and T H 17 Responses in Human Emphysema

Specialized immune cells in the lungs of patients with emphysema create an inflammatory environment that drives lung destruction in a characteristic autoimmune reaction. Dendritic Cells of Destruction Underlie Emphysema Tobacco smoke is never good for your lungs, and in some people it sets up a destructive process called emphysema. In this disease, air sacs that normally exchange carbon dioxide for oxygen become enlarged, ultimately losing their elastic recoil and physiological function. Breathing becomes labored. Even uninfected lungs with emphysema show signs of a complex immune response, with an accumulation of immune cells. To attack the difficult chicken-or-the-egg problem presented by this disease, Shan et al. sorted out which of these cells serve as the ringleaders in orchestrating this immune reaction and, in the process, found the telltale presence of T helper 17 (TH17) cells—a recently identified hallmark of autoimmune inflammation. Cigarette smoke causes irritation in the lung and activates a general defensive reaction via the innate immune system. When this system cannot restore tissue health, the more precise adaptive immune system comes into play. The authors of Shan et al. now show that specialized professional antigen-presenting cells—called dendritic cells—are recruited by a chemoattractant into the lung, where they induce naïve CD4 T cells to develop into TH1 cells. These immune agents then help cytotoxic T cells to target damaged host lung tissue for destruction. Also induced by the dendritic cells are TH17 cells. These specialized T lymphocytes normally protect the barriers between the body and the environment (the skin and the gut lining, for example), but they also congregate at sites in which the body is erroneously attacking itself, as in autoimmune diseases such as rheumatoid arthritis and colitis. The cytokine interleukin-17A secreted by the TH17 cells coordinates their contribution to destruction of the lung in emphysema by causing lung macrophages to secrete two critical molecules: CCL20, a chemoattractant for the dendritic cells, which then set up an inflammatory positive feedback loop, and matrix metalloproteinase 12 (MMP12), a potent enzyme that destroys a lung endogenous protective proteinase called α1-antitrypsin. In the industrialized world, the ultimate cause of emphysema is usually smoking, but in developing countries, smoke from cooking fires and pollution are important factors in the development of this disease, which is a leading cause of death worldwide. Even after removal of the respiratory irritant, the disease progression is only slowed and existing lung damage is irreversible. Medications can ease the shortness of breath but are not a cure. A lung transplant or partial lung removal is a last resort available only to a few fortunate individuals (see Cypel et al. in this issue). Identification of the cellular players—like the dendritic and TH17 cells described by Shan et al.—through which smoke causes lung destruction is a key to discovering drugs that effect damage control. Moreover, the injurious cellular cycles established in the emphysematous lung are likely not unique, and their elucidation will undoubtedly uncover clues to other immune-related diseases that are associated with smoking. Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.

On-Pump Versus Off-Pump Coronary Artery Bypass Grafting in a Cohort of 63,000 Patients

BACKGROUND The best approach to surgical myocardial revascularization remains controversial. We compared outcomes of conventional on-pump coronary artery bypass grafting (CABG) and off-pump coronary artery bypass (OPCAB) by using a nonvoluntary national database. METHODS In the 2004 Nationwide Inpatient Sample database, we identified 63,047 discharge records of patients who underwent CABG (n = 48,658) or OPCAB (n = 14,389). We analyzed seven preoperative variables, including the Deyo comorbidity index and five outcome measures. Multivariable logistic regression was used to identify independent predictors of outcomes. RESULTS CABG and OPCAB patients had similar demographics and comorbidities. They also had similar rates of in-hospital mortality (3.0% vs 3.2%; p = 0.14) and postoperative stroke (1.8% vs 1.7%; p = 0.53). However, OPCAB patients had longer hospital stays (10.2 +/- 9.4 vs 9.9 +/- 8.5 days; p < 0.0001) and higher hospital costs (

Does the Level of Experience of Residents Affect Outcomes of Coronary Artery Bypass Surgery

38,793 +/-

Treatment of combined coronary and carotid artery disease.

30,830 vs

Endovascular versus open repair of ruptured descending thoracic aortic aneurysms: A nationwide risk-adjusted study of 923 patients

37,806 +/-

Transverse sternal plating in secondary sternal reconstruction

28,705; p = 0.0005) than CABG patients. Multivariable regression analysis showed that OPCAB independently predicted 0.6 more days of hospital stay (95% confidence interval [CI], 0.4 to 0.8 day; R(2) = 0.09; p < 0.0001) and

Endovascular repair of ascending aortic pseudoaneurysm: technical considerations of a common carotid artery approach using the Zenith aortic cuff endograft.

1,497 more in hospital costs (95% CI,