JCI online early table of contents: Feb. 9, 2009

Ariela Benigni and colleagues, at the "Mario Negri" Institute for Pharmacological Research, Italy, have found that mice lacking the protein AT1A live substantially longer than normal mice. As drugs that antagonize AT1A are currently used to treat high blood pressure and heart failure, the authors suggest that future studies should investigate whether such drugs prolong life in humans. Further analysis revealed that the increased lifespan in mice lacking AT1A was likely a result of decreased oxidative damage to cells, a key factor in ageing, and increased levels of genes involved in cell survival (such as Sirt3).

TITLE: Disruption of the Ang II type 1 receptor promotes longevity in mice

AUTHOR CONTACT:
Ariela Benigni
"Mario Negri" Institute for Pharmacological Research, Bergamo, Italy.
Phone: 39-035-319-888; Fax: 39-035-319-331; E-mail: abenigni@marionegri.it.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36703

Understanding what molecular pathways control the release of hematopoietic stem cells (i.e., the stem cells that give rise to all blood cells) from the bone marrow has immense relevance to a number of clinical situations, including stem cell transplantation and post-chemotherapy treatment regimens. New insight into the molecules involved in regulating the movement of human hematopoietic progenitor cells from the bone marrow, provided by the work of Tsvee Lapidot and colleagues, at the Weizmann Institute of Science, Israel, might provide clues to developing new ways to enhance stem cell release from the bone marrow.

In the study, CD34+ hematopoietic progenitor cells in the bloodstream of healthy individuals were found to express higher levels of the protein MT1-MMP and lower levels of the protein RECK than their precursor cells in the bone marrow. Further, when healthy individuals were treated with a drug that stimulates the release of hematopoietic progenitor cells from the bone marrow, the circulating cells expressed even higher levels of MT1-MMP. Further analysis in mice with bone marrow reconstituted with human cells, revealed that blocking MT1-MMP function impaired the release of human hematopoietic progenitor cells from the bone marrow and that blocking RECK function enhanced the release of these cells. Additional experiments determined that MT1-MMP promotes the release of hematopoietic progenitor cells from the bone marrow by cleaving a protein known as CD44. The authors conclude that MT1-MMP and RECK have opposing roles in the control of human hematopoietic progenitor cell egress from the bone marrow.

TITLE: MT1-MMP and RECK are involved in human CD34+ progenitor cell retention, egress, and mobilization

AUTHOR CONTACT:
Tsvee Lapidot
Weizmann Institute of Science, Rehovot, Israel.
Phone: 972-8-9342481; Fax: 972-8-9344141; E-mail: tsvee.lapidot@weizmann.ac.il.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36541

The drug eptifibatide interferes with blood clotting and is used to treat a number of serious heart conditions associated with a high risk of heart attack. Despite the effectiveness of eptifibatide and other related drugs, in a few individuals they cause serious side effects, including thrombocytopenia (a deficiency in blood cells known as platelets, which are important for blood clotting). Peter Newman and colleagues, at the BloodCenter of Wisconsin, Milwaukee, have now provided new insight into the molecular mechanisms by which eptifibatide induces thrombocytopenia.

Eptifibatide works by antagonizing a protein complex known as integrin alpha-IIb-beta-3. The rare cases of thrombocytopenia in patients treated with eptifibatide are caused by antibodies, generated by the immune system of the patients, that recognize the drug bound to integrin alpha-IIb-beta-3. In the study, the authors analyzed the effects of patient serum containing an alpa-IIb-beta-3-specific, eptifibatide-dependent antibody on normal human platelets. In the presence of eptifibatide, the antibodies caused the platelets to become activated. Further analysis revealed that activation was mediated via a signaling pathway initiated by Fc-gamma-RIIa and beta-3 integrin. These data provide a mechanism that explains how alpa-IIb-beta-3-specific, eptifibatide-dependent antibodies can cause thrombocytopenia.

TITLE: Eptifibatide-induced thrombocytopenia and thrombosis in humans require Fc-gamma-RIIa and the integrin beta-3 cytoplasmic domain

AUTHOR CONTACT:
Peter J. Newman
BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA.
Phone: (414) 937-6237; Fax: (414) 937-6284; E-mail: peter.newman@bcw.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36745

Pulmonary hypertension is the name given to the potentially fatal condition of high blood pressure in the vessels that carry blood from the heart to the lung, where the blood replenishes its supply of oxygen, and back. It is characterized by the proliferation of a subset of cells in the wall of the blood vessel going from the heart to the lung that are known as pulmonary artery smooth muscle cells (PA-SMCs). While the lung endothelium (the layer of cells that lines the blood vessels going to and from the lung) is thought to influence this process, its role has not been well understood. In a new study, Saadia Eddahibi and colleagues, at INSERUM U841, France, have revealed the role of a specific protein, FGF2, in the endothelial response during pulmonary hypertension.

The lung endothelium of patients with pulmonary hypertension had increased FGF2 production compared to healthy controls. Moreover, PA-SMCs treated with media from cultured patient endothelial cells experienced greater proliferation than PA-SMCs treated with media from healthy control individuals. This proliferation was blocked by approaches that inhibited FGF2, both in cultured cells and in a rat model of pulmonary hypertension. The authors therefore conclude that FGF2 may serve as a novel target in the treatment of pulmonary hypertension.

TITLE: Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents

AUTHOR CONTACT:
Saadia Eddahibi
INSERM U841, Créteil, France.
Phone: 33-149-813-613; Fax: 33-148-981-777; E-mail: saadia.eddahibi@inserm.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35070

Chronic obstructive pulmonary disease (COPD) is a progressive disease of the lung and the fourth leading cause of death in the United States. Although recent studies suggest immune cells known as lymphocytes contribute to the chronic airway inflammation that is associated with COPD, there is no evidence that they are involved in the development of the disease. However, Michael Borchers and colleagues, at the University of Cincinnati College of Medicine, Cincinnati, have now determined that a subset of lymphocytes known as CTLs do contribute to the development of COPD-like disease in mice.

In the study, in vivo and in vitro exposure of the lining of the mouse airway to cigarette smoke induced the airway lining to express a protein known as RAET1, which binds the protein NKG2D on CTLs, activating them. Consistent with CTLs having a role in the development of COPD, induction of RAET1 expression in the lining of mouse airways, induced COPD-like disease that was reversible by blocking NKG2D. As the authors found increased expression of a protein that binds human NKG2D in lung tissue from smokers with normal lung function, and current and former smokers with COPD, but not in lung tissue from individuals who had never smoked, they suggest that persistent expression of proteins that bind NKG2D in the cells lining the lungs and airways contributes to the development of COPD via activation of CTLs.

TITLE: Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease

AUTHOR CONTACT:
Michael T. Borchers
University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Phone: (513) 558-6424; Fax: (513) 558-0925; E-mail: michael.borchers@uc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34462