EDITOR'S PICK: Broccoli-based compound beats drug resistance in lung disease
Chronic obstructive pulmonary disease (COPD) is a common lung disease that gets progressively worse over time, making it harder and harder to breathe. It is caused primarily by cigarette smoking, which leads to persistent inflammation in the airways and the subsequent destruction of the lung tissue. Given the central role of inflammation in COPD, it is surprising that patients derive little benefit from treatment with potent anti-inflammatory drugs known as corticosteroids. Working with cells from individuals with COPD, a team of researchers led by Shyam Biswal and Rajesh Thimmulappa, at Johns Hopkins University, Baltimore, has identified a candidate therapeutic that could potentially be used to augment the anti-inflammatory effects of corticosteroids in individuals with COPD -- sulforaphane, a compound obtained from cruciferous vegetables such as broccoli, Brussels sprouts, and cabbages.
TITLE: Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients
AUTHOR CONTACT:
Shyam Biswal
Johns Hopkins University, Baltimore, Maryland, USA.
Phone: 410-502-1944; Fax: 410-955-0116; E-mail: sbiswal@jhsph.edu.
Rajesh Thimmulappa
Johns Hopkins University, Baltimore, Maryland, USA.
Phone: 410-502-1949; Fax: 410-955-0116; E-mail: rthimmul@jhsph.edu.
View this article at: http://www.jci.org/articles/view/45144?key=7054ccb1c3b0d46eee8d
HEMATOLOGY: Linking high levels of blood glucose to complications of diabetes
The number of individuals with type 2 diabetes is reaching epidemic proportions. Among the complications of type 2 diabetes is increased morbidity and mortality from cardiovascular disease (a group of diseases of the heart or blood vessels that includes those that cause heart attack and stroke). One of the reasons for this is that platelets (cells key to the blood clotting process) are hyperreactive in individuals with type 2 diabetes. A team of researchers led by John Hwa, at Yale University School of Medicine, New Haven, has now defined the signaling pathway that links the high levels of glucose in the blood of individuals with type 2 diabetes to platelet hyperreactivity. The pathway includes multiple potential targets for therapeutics that could inhibit the activation of platelets by high levels of blood glucose, including the protein aldose reductase.
TITLE: Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane
AUTHOR CONTACT:
John Hwa
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-737-5583; Fax: 203-737-6118; E-mail: John.Hwa@yale.edu.
View this article at: http://www.jci.org/articles/view/59291?key=fc6e3b3e6ecd34267e2f
ALLERGY AND ASTHMA: The bell Toll's for asthma
The number of people with asthma has increased sharply over the past few decades. A team of researchers led by Cory Hogaboam and Ana Paula Moreira, at the University of Michigan Medical School, Ann Arbor, has obtained data from two mouse models of asthma that lead them to suggest a potential new approach to treating clinical asthma.
Asthma symptoms are triggered in sensitive people when they breathe in allergy-causing substances (allergens). Among the most common allergens are pollen, pet hair, dust mites, and fungi. Clinical data suggest that the protein Toll-like receptor 6 (TLR6) has protective effects in asthma. To investigate this further, Hogaboam, Moreira, and colleagues examined the role of TLR6 in the development and maintenance of experimental asthma. They found that the presence of TLR6 reduces the severity of disease in mouse models of asthma induced by either fungi or house dust mites and identified the mechanisms by which TLR6 exerts its protective effects. They therefore suggest that therapeutics triggering TLR6 activity might be of benefit to individuals with asthma.
TITLE: The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A
AUTHOR CONTACT:
Cory M. Hogaboam
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: 734-647-8153; Fax: 734-615-8166; E-mail: hogaboam@med.umich.edu.
Ana Paula Moreira
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: 734-936-1856; Fax: 734-936-7996; E-mail: anapaula@umich.edu.
View this article at: http://www.jci.org/articles/view/44999?key=9eced6059dab0755b735
HIV/AIDS: How to enhance the immune response to HIV
In individuals infected with HIV, progression to AIDS is characterized by depletion of immune cells known as CD4+ T cells. Surprisingly, however, the extent to which CD4+ T cells contribute to the anti-HIV immune response has not been determined. A team of researchers led by Guido Silvestri, at Emory University School of Medicine, Atlanta, has now investigated this issue in rhesus macaques infected with the monkey equivalent of HIV (SIV). The data generated by the team indicate that CD4+ T cells are essential in establishing control of SIV replication during acute infection. As the majority of candidate HIV vaccines focus on triggering anti-HIV immune responses from immune cells other than CD4+ T cells (predominantly CD8+ T cells and B cells), Silvestri and colleagues suggest that their data provide rationale for including in candidate HIV vaccines a component that stimulates CD4+ T cells.
TITLE: Depletion of CD4+ T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques
AUTHOR CONTACT:
Guido Silvestri
Yerkes National Primate Research Center and Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: 404-727-9139; Fax: 404-727-9139; E-mail: gsilves@emory.edu.
View this article at: http://www.jci.org/articles/view/46023?key=95c7c68d055283ce9630
PULMONARY: Inhibiting the protein calpain: a breath of fresh air in pulmonary hypertension
Pulmonary arterial hypertension (PAH) is the medical term given to increased pressure in the arterial blood vessels that carry blood from your heart to your lungs to pick up oxygen (the pulmonary arteries). It is a progressive disease that causes shortness of breath, tiredness, chest pain, and a racing heartbeat; it culminates in failure of the right side of the heart. There are no cures and a lung transplant is often necessary. However, a team of researchers led by Yunchao Su, at Georgia Health Sciences University, Augusta, has now identified in rodent models of PAH the protein calpain as a potential therapeutic target for the treatment of PAH.
Central to PAH are changes in the lining of the pulmonary arteries that makes them less elastic. These changes occur during a process known as pulmonary vascular remodeling. Su and colleagues found that calpain had a key role in pulmonary vascular remodeling in two rodent models of PAH. Importantly, disease was abrogated in rats treated with an inhibitor of calpain. The finding that pulmonary arterioles from patients with PAH had elevated levels of calpain activation provide further support for the suggestion of Su and colleagues that inhibiting this protein could prove beneficial to individuals with PAH.
TITLE: Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease
AUTHOR CONTACT:
Yunchao Su
Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia, USA.
Phone: 706-721-7641; Fax: 706-721-2347; E-mail: ysu@georgiahealth.edu.
View this article at: http://www.jci.org/articles/view/57734?key=833653d452ef09e35e6e
IMMUNOLOGY: Stopping progression to shock in its tracks
Systemic inflammatory response syndrome (SIRS) is an inflammatory condition that affects the whole body. It is a potentially lethal condition because it can progress to shock, multi-organ failure, and death. The chain of events that causes SIRS to progress to shock is not well defined, unraveling it could provide targets for therapeutic intervention. A team of researchers led by Ricky Cheung and Robert Pierce, at Merck Research Laboratories, Palo Alto, has now identified triggering of the protein MDL-1 on immune cells known as immature myeloid cells as critical in the progression of SIRS to shock in mice in which SIRS was provoked by liver damage caused by the compound ConA. Inhibiting molecules determined to be in the signaling pathway activated by triggering MDL-1 protected the mice from shock. Cheung, Pierce, and colleagues therefore suggest that targeting the signaling pathway activated by triggering MDL-1 could provide a new approach to prevent the progression of SIRS to shock.
In an accompanying commentary, Peter Ward, at the University of Michigan Medical School, Ann Arbor, discusses in detail the broad mechanistic and therapeutic implications of the data generated by Cheung, Pierce, and colleagues.
TITLE: Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice
AUTHOR CONTACT:
Ricky Cheung
Merck Research Laboratories, Palo Alto, California, USA.
Phone: 650-496-1276; Fax: 650-496-1200; Email: ricky.cheung@utoronto.ca.
Robert H. Pierce
Merck Research Laboratories, Palo Alto, California, USA.
Phone: 650.496.6528; Fax: 650-496-1200; E-mail: robert.pierce@merck.com.
View this article at: http://www.jci.org/articles/view/57682?key=b464fb97caa5dbb4e2a8
ACCOMPANYING COMMENTARY TITLE: Do MDL-1+ cells play a broad role in acute inflammation?
AUTHOR CONTACT:
Peter A. Ward
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: 734-647-2921; Fax: 734-764-4308; E-mail: pward@umich.edu.
View this article at: http://www.jci.org/articles/view/60122?key=b7fd7173c7e50dd758a0
GASTROENTEROLOGY: Th2-type immunity bungs up the bile ducts
Biliary atresia is a severe congenital disease (i.e., it is present from birth) in which there is a blockage in the tubes (ducts) that carry a liquid called bile from the liver to the gallbladder. The inability of bile to flow from the liver to the gallbladder can lead to liver damage and cirrhosis of the liver, which is deadly if not treated. Th1-type immune responses have been linked to the bile duct inflammation and obstruction that occurs in biliary atresia. Now, a team of researchers led by Jorge Bezerra, at Cincinnati Children's Hospital Medical Center, Cincinnati, has linked Th2-type immune responses to bile duct obstruction in a mouse model of biliary atresia. Importantly, analysis of infants at the time of diagnosis with biliary atresia indicated that they could be divided into subgroups of those with high expression of Th2 genes and immune mediators and those with low expression. Bezerra and colleagues therefore suggest that patients should be subgrouped by Th2 status in clinical trials testing candidate treatments for biliary atresia, especially those designed to modulate the immune system, to ensure that these differences can be factored into determining the success of the candidate treatment.
TITLE: Th2 signals induce epithelial injury in mice and are compatible with the biliary atresia phenotype
AUTHOR CONTACT:
Jorge A. Bezerra
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: 513-636-3008; Fax: 513-636-5581; E-mail: jorge.bezerra@cchmc.org.
View this article at: http://www.jci.org/articles/view/57728?key=193d60312707c3100e23
Journal
Journal of Clinical Investigation