Drawing a crowd: understanding the signals that bring inflammatory cells into the lung
Understanding the connection between influx of immune cells into the lung and acute lung injury is essential, since lung damage tends to occur secondary to increased lung inflammation. In a study appearing online on February 16 in advance of print publication in the March issue of the Journal of Clinical Investigation, Klaus Ley and colleagues from the University of Virginia in Charlottesville demonstrate that expression of an immune molecule called CXCR2 on blood vessel wall cells (as opposed to immune cells themselves) mediates the influx of white blood cells, called neutrophils, into the lung during acute bacterial infection. The researchers stimulated neutrophil influx to the lungs of mice by having the mice breathe in a bacterial sugar called lipopolysaccharide (LPS). As expected, mice that were genetically modified so that they did not express CXCR2 (called CXCR2 knockout mice) failed to recruit neutrophils. However, the authors were surprised to find that normal mice whose normal bone marrow cells (ie., immune cells) were replaced with cells from the CXCR2 knockout mice were able to recruit neutrophils to the lung at a rate of about 50% of normal, suggesting that even though the knockout neutrophils did not have CXCR2, they were still able to migrate to the lung. Using a specific antibody that detects CXCR2 protein, the researchers found that CXCR2 is present on blood vessel wall cells of the lung and in cells called epithelial cells that line the airways. The authors report that it is this pattern of CXCR2 expression on lung cells, and not the presence of CXCR2 on the neutrophils themselves, which is essential for neutrophil recruitment in response to LPS and the resulting acute lung injury.
TITLE: Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung
University of Virginia, Charlottesville, Virginia, USA
Phone: (434) 243-9966; Fax: (434) 924-2828; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=27009
Outfoxing diabetes and insulin resistance
Diabetes is a disease caused by the inability of the body to produce or respond to insulin (insulin resistance), and the main cells that fail in this disease are insulin-producing cells of the pancreas called beta cells. Although beta cells are renewed during adult life, during insulin resistant states the beta cells become hyperplastic (making too many cells) to compensate for their impaired function. Unfortunately, the mechanism for this hyperplasia is unclear. Now, in a study appearing online on February 16 in advance of print publication in the March issue of the Journal of Clinical Investigation, Domenico Accili and colleagues from Columbia University in New York report that a protein called FoxO1 is involved in regulating beta cell numbers during insulin resistance. The authors created genetically modified "transgenic" mice that overexpress a mutant form of FoxO1 that is always active in the nucleus of the beta cells and found that the proliferation of these cells in response to insulin resistance was prevented. However, there was no effect on insulin secretion, demonstrating that levels of insulin increased to compensate for the failure to increase beta cell number. Importantly, FoxO1 was found to be necessary for existing beta cell numbers to increase during insulin resistance, but was not necessary for precursor cells (pre-beta cells) to turn into beta cells. These data suggest that continuous expression of FoxO1 in the nucleus of beta cells prevent their hyperplasia, and can accelerate the onset of diabetes, even in the presence of sufficient insulin production. The authors state that these data indicate that FoxO1 signaling is an integral part of the beta cell response to insulin resistance.
TITLE: Role of the forkhead protein FoxO1 in beta cell compensation to insulin resistance
Columbia University, New York, New York, USA
Phone:(212)851-5332; Fax:(212)851-5331; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24967
When going backwards is good: reversing fatty liver disease and insulin resistance in rats
The most frequent cause of abnormal liver function tests in the United States is nonalcoholic fatty liver disease (NAFLD), caused by the build up of fats called triglycerides in the liver. Severe cases of NAFLD are associated with steatohepatitis, in which the liver progresses to end-stage liver disease requiring transplant. Interestingly, this disorder is also associated with insulin resistance, and therefore contributes to diabetes. In a study reported online on February 16 in advance of print publication in the March issue of the Journal of Clinical Investigation, Gerald I. Shulman and colleagues from Yale Medical School in Connecticut, provide clear evidence that inhibiting acetyl-CoA carboxylases or "Acc" (molecules involved in fatty acid synthesis) reverses both the steatosis and insulin resistance of the liver. The researchers used a technique involving small inhibitors of gene expression called "antisense oligonucleotides" to block Acc1, Acc2, or both Acc genes in rats and found that the use of fat as fuel in the liver was increased. In addition, suppressing Acc1 in rats with NAFLD inhibited the synthesis of new lipids, and did so more efficiently that suppressing Acc2. Suppressing both Acc genes significantly improved liver insulin sensitivity in NAFLD rats. The authors suggest that pharmacological inhibition of Acc1 and Acc2 may be an important strategy in the treatment of patients with hepatic insulin resistance and NAFLD.
TITLE: Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2.
Gerald I. Shulman
Yale Medical School, New Haven, Connecticut, USA
Phone:(203)785-5447; Fax:(203)737-4059; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=27300
A potential tool in the fight to reduce the symptoms of sickle cell disease
Vaso-occlusion is the major cause of morbidity and mortality in sickle cell disease (SCD), and occurs when the blood protein hemoglobin S (HbS) forms polymeric fibers causing the blood to become more viscous and impair flow (stasis). Although the genetic causes of SCD are known, there is still a gap in the understanding of the mechanisms involved in vaso-occlusion. In a study appearing online on February 16 in advance of print publication in the March issue of the Journal of Clinical Investigation, John D. Belcher and colleagues from the University of Minnesota show that a protein called heme oxygenase-1 (HO-1) can reduce inflammation and inhibit vaso-occlusion in mice that have SCD. The researchers examined the blood vessels of SCD mice and found that HO-1 was increased in response to an increased heme burden, suggesting that HO-1 responds to elevated levels of iron (and hence oxidative stress) in the blood. Using antibodies that recognize the HO-1 protein, the authors found elevated levels of HO-1 in the livers, lungs, and spleens of SCD mice, compared to normal mice. The authors also discovered that HO-1 can inhibit the binding of white blood cells to the vessel wall and can prevent stasis that is induced by low oxygen/restored oxygen cycles. These findings suggest that agents that increase HO-1 activity may be an important new method to prevent or reduce the painful vaso-occlusion in SCD patients.
TITLE: Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice
John D. Belcher
University of Minnesota, Minneapolis, Minnesota, USA
Phone:(612)624-2611; Fax:(612)625-6919; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=26857
A BAFFling issue for B cells in autoimmune disease
A promising treatment for autoimmune diseases is blockade of the activity of B cells of the immune system, since these cells produce tissue-damaging autoantibodies (self-attacking proteins) and inflammatory mediators. Blocking the binding of a B cell survival protein called BAFF to its three B cell receptors (TAC1, BCMA, and BAFF-R) prevents autoimmune disease in animals, and several BAFF inhibitors are under study in early human clinical trials. However, controversy exists as to whether autoimmune disease therapy should consist of blocking only BAFF (selective blockade) or BAFF and another molecule called APRIL (nonselective blockade), which binds only to the TAC1 and BCMA receptors. Now, researcher Anne Davidson and colleagues at Columbia University show that while both treatments reduce B cell numbers and prolong the lives of mice with lupus, they may have very different applications in human disease. The authors of the study infected lupus-afflicted mice with a virus that neutralized BAFF. The mice demonstrated reduced disease severity, less inflammation in the kidney, but also exhibited an impaired ability to respond to bacterial infection. Additionally, the researchers report that selective BAFF blockade combined with a molecule known as CTLA4 to inhibit activation of special immune cells called T cells was able to induce complete remission of autoimmunity in mice with established disease. The researchers suggest that APRIL blockade may be better therapy for diseases caused by short-lived antibody-producing B cells. In addition, the authors state that these results have implications for the therapeutic potential of these molecules as targets in autoimmune disease as well as B cell cancers, but that care should be taken to prevent significant immunosuppression in patients. The study will appear online on February 16 in advance of print publication in the March issue of the Journal of Clinical Investigation.
TITLE: Similarities and differences between selective and nonselective BAFF blockade in murine SLE
Columbia University, New York, New York, USA
Phone: 212-851-4571; Fax: 212-851-4548; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26385
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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