Topical Treatment Improves Wound Healing
A group led by Dr. Yasunori Okada at Keio University in Tokyo, Japan has demonstrated that matrix metalloproteinases (MMPs) are instrumental in wound healing. Their report can be found in the August 2009 issue of The American Journal of Pathology.
Wound healing is the complex process of regenerating dermal and epidermal tissue after skin injury. MMPs, which can degrade proteins, are essential in breaking down wounded tissues to allow for wound healing; however, the specific function of individual MMPs in wounded tissues requires further study.
Using mouse models that lacked individual MMPs, Hattori et al noted that wound closure in MMP-deficient mice was significantly delayed compared with normal mice. Both MMPs examined played key roles in movement of skin cells, and one contributed to new blood vessel growth as well. Topical treatment with MMPs increased the rate of wound healing in these mice, providing a possible therapeutic strategy for treating delayed wound healing.
Dr. Okada and colleagues "have provided the first evidence of the importance of MMP-9 and MMP-13 on cutaneous wound healing by demonstrating that [mice that lack either] MMP-9, MMP-13, or both MMP-9/13 exhibit a significant delay in macroscopic wound closure and histological re-epithelialization. … [Their data] suggest the possible treatment of delayed wound healing by the application of the MMPs or inducers of the MMPs."
Hattori N, Mochizuki S, Kishi K, Nakajima T, Takaishi H, D'Armiento J, Okada Y: MMP-13 plays a role in keratinocyte migration, angiogenesis, and contraction in mouse skin wound healing. Am J Pathol 2009, 175: 533-546
FUT-175 Complements Experimental Autoimmune Encephalomyelitis (EAE)
Dr. Feng Lin and colleagues at Case Western Reserve University in Cleveland, OH have discovered that the complement inhibitor FUT-175 delays EAE onset. They present these findings in the August 2009 issue of The American Journal of Pathology.
Multiple sclerosis (MS) is an autoimmune disease in which the body's immune response attacks the central nervous system (CNS), causing physical and cognitive disability. Complement, molecules involved in clearing infection, may enhance this misguided immune response.
Li et al therefore examined the effects of FUT-175, a drug with few clinical side effects that prevents the functions of complement, on the development of EAE, a mouse model of MS. They found that FUT-175 prevented production of activated complement and inhibited specific immune responses with little non-specific toxicity. FUT-175 treatment delayed EAE disease onset and decreased the severity of disease. Thus, FUT-175 may be a novel candidate to treat autoimmune diseases such as MS.
This study by Li et al "provide[s] further insight into how to most effectively apply … complement inhibitors for treating T cell-mediated diseases."
Li Q, Nacion K, Bu H, Lin F: The complement inhibitor FUT-175 suppresses T cell autoreactivity in experimental autoimmune encephalomyelitis. Am J Pathol 2009, 175: 661-667
New Target for Tumor Angiogenesis Inhibition
Researchers led by Dr. Horace DeLisser at the University of Pennsylvania School of Medicine in Philadelphia, PA have found that loss of PECAM-1 (Platelet Endothelial Cell Adhesion Molecule-1) inhibits tumor angiogenesis. They report their data in the August 2009 issue of The American Journal of Pathology.
During angiogenesis, new blood vessels grow from existing blood vessels. Angiogenesis plays a key role in tumor malignancy, but its role in normal growth and development leads to toxicity in anti-angiogenesis cancer therapies.
Antibodies against PECAM-1, a molecule expressed on multiple blood vessel-associated cells, impair blood vessel formation. Cao et al further examined the role of PECAM-1 in angiogenesis using mice that lacked PECAM-1. Tumor angiogenesis was inhibited when endothelial cells, which line blood vessels, did not express PECAM-1, and these PECAM-1-negative endothelial cells had decreased signs of motility, which is important for new blood vessel formation. As PECAM-1 is not required for blood vessel development in the embryo, PECAM-1 may therefore provide a tumor-specific, low toxicity target to inhibit angiogenesis in cancer patients.
Dr. DeLisser and colleagues conclude that "given its potential role in protecting against endotoxic and apoptotic stresses, and as a mediator of leukocyte recruitment, human clinical trials will be required to establish the ultimate safety of therapy targeted against PECAM-1. In this regard, further studies with the goal of specifically defining the role of PECAM-1 as a facilitator of endothelial cell motility will be very important."
Cao G, Fehrenbach ML, Williams JT, Finklestein JM, Zhu J-X, DeLisser HM: Angiogenesis in PECAM-1-null mice. Am J Pathol 2009, 175: 903-915
Treating Liver High Blood Pressure
Dr. Yasuni Nakanuma and colleagues of Kanazawa University Graduate School of Medicine in Kanazawa, Japan have discovered that BMP-7 (bone morphogenic protein-7) is a potential new therapy for treating high blood pressure in the liver. These results are presented in the August 2009 issue of The American Journal of Pathology.
Idiopathic portal hypertension (IPH) is a form of high blood pressure that often results from blockage of the peripheral veins in the liver. Cells that line blood vessels (endothelial cells) undergo endothelial-mesenchymal transition (EMT) to become more mobile; these cells may contribute to the fibrosis that causes IPH-associated blockage.
Kitao et al demonstrated that a molecule that contributes to the fibrotic process, TGF-β1 (transforming growth factor-β1), can induce EMT and that BMP-7, a member of the TGF-b superfamily, can preserve the endothelial phenotype. Indeed, patients with IPH have elevated levels of TGF-β1, but no difference in levels of BMP-7 compared with healthy controls. TGF-b and BMP-7 may therefore provide a potential target and agent, respectively, for treating IPH.
Kitao et al "suggest that EMT of the portal vein endothelium via TGF-β1/Smad activation is closely associated with the pathogenesis of portal venous stenosis of IPH … [and that] BMP7 may act as an inhibitor of EndMT by antagonizing the effects of TGF-β1."
Kitao A, Sato Y, Kitamura S, Harada K, Sasaki M, Morikawa H, Shiomi S, Honda M, Matsui O, Nakanuma Y: Endothelial to mesenchymal transition via transforming growth factor-b1/Smad activation is associated with portal venous stenosis in idiopathic portal hypertension. Am J Pathol 2009, 175: 616-626
Neural Progenitors Drive Neuroblastoma Initiation and Progression
A group led by Dr. Han-Fei Ding of the Medical College of Georgia in Augusta, GA reports that the oncogene MYCN may drive neuronal progenitor cell proliferation, contributing to neuroblastoma development. This study can be found in the August 2009 issue of The American Journal of Pathology.
Neuroblastomas are the most common cancer in infancy, and nearly 50% of neuroblastomas occur in children under the age of two. Approximately 22% of neuroblastomas, which commonly contain undifferentiated or poorly differentiated neuroblasts, express amplified levels of the oncogene MYCN.
To identify the cell types that drive neuroblastoma development and the role of MYCN in this process, Alam et al examined mice that express MYCN in neural cells; these mice provide an animal model of human neuroblastoma. MYCN expression caused neuronal progenitors to divide as well as prevented their differentiation into more mature cells, and primary tumors were composed predominantly of these cells. These data indicate that the expansion of these neuronal progenitors may be pathogenic in the development of neuroblastoma and that MYCN may contribute to this process by driving the proliferation of the neuronal progenitor cell population.
Dr. Ding and colleagues postulate that "cooperation between oncogenic proteins and lineage-determining factors might be an important mechanism underlying the development of tissue-type specific tumors."
Alam G, Cui H, Shi H, Yang L, Ding J, Mao L, Maltese WA, Ding H-F: MYCN promotes the expansion of Phox2B-positive neuronal progenitors to drive neuroblastoma development. Am J Pathol 2009, 175: 856-866
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