Susan from the ILD Support Group sent this e-mail to the group. I thought they were both interesting enough to pass them along to you, dear reader. Both articles are posted at the Pulmonary Fibrosis Foundation website.
Study points to a phosphorylation pathway that may contribute to the development of lung injury and fibrosis
A study by researchers at the University of California, San Diego School of Medicine may lead to a way to prevent the progression, or induce the regression, of lung injury that results from use of the anti-cancer chemotherapy drug Bleomycin. Pulmonary fibrosis caused by this drug, as well as Idiopathic Pulmonary Fibrosis (IPF) from unknown causes, affect nearly five million people worldwide. No therapy is known to improve the health or survival of patients.
Their research shows that the RSK-C/EBP£]ƒnphosphorylation pathway may contribute to the development of lung injury and fibrosis, and that blocking this phosphorylation ¡V a regulatory mechanism in which proteins and receptors are switched on or off ¡V improved Bleomycin-induced lung fibrosis in mice. The study appears on-line October 5 in Proceedings of the Library of Science (PloS ONE).
Bleomycin is a common chemotherapy drug used to treat many forms of cancer, according to study authors Martina Buck, PhD, associate professor of medicine, and Mario Chojkier, MD, professor of medicine, both researchers at UC San Diego Moores Cancer Center and the VA San Diego Healthcare System. ¡§Unfortunately, use of Bleomycin has damaging side effects, including lung fibrosis. We are hopeful that this discovery could provide a way to stop such lung damage so that cancer patients could better tolerate this chemotherapy,¡¨ said Buck.
The downstream molecular mechanism that causes Bleomycin-induced lung fibrosis remained unknown. The scientists set out to identify the specific signaling involving a single amino acid within a specific domain of one protein that could be blocked the half the progression of such injury, in order to design effective targeted therapeutics.
They found that blocking RSK phosphorylation of a binding protein called C/EBP-Beta on the RSK macromolecule Thr217 with either a single point mutation or a blocking peptide ameliorated the progression of lung injury and fibrosis induced by Bleomycin in mice.
¡§We hypothesized that this pathway was critical given similarities between liver and lung fibrogenesis. RSK plays an important role in both the macrophage inflammatory function and survival of activated liver myofibroblasts ¡V cells that contribute to maintenance and tissue metabolism,¡¨ said Buck. ¡§Therefore, we proposed that a similar signaling mechanism is also responsible for lung injury and fibrosis.¡¨
By identifying the peptide that shuts down this process, the researchers were essentially able to sequester a small piece of an important regulatory protein, C/EBP Beta, responsible for fibrosis, thereby stopping phosphorylation. ¡§Basically, the kinase protein gets hung up, trying again and again ¡V unsuccessfully ¡V to ¡¥turn on¡¦ the fibrous growth,¡¨ Buck added.
In addition, phosphorylation of human C/EBP£] was induced inƒnhuman lung fibroblasts in culture and in situ in lungs of patients with severe lung fibrosis, but not in control lungs, suggesting that this signaling pathway may be also relevant in human lung injury and fibrosis.
The researchers add that it is premature to assess whether this pathway will provide an effective therapeutic target. However, blocking progression of lung fibrosis could decrease the need for lung transplantation, since IPF is the main indication for lung transplants worldwide.
A study by researchers at the University of California, San Diego School of Medicine may lead to a way to prevent the progression, or induce the regression, of lung injury that results from use of the anti-cancer chemotherapy drug Bleomycin. Pulmonary fibrosis caused by this drug, as well as Idiopathic Pulmonary Fibrosis (IPF) from unknown causes, affect nearly five million people worldwide. No therapy is known to improve the health or survival of patients.
Their research shows that the RSK-C/EBP£]ƒnphosphorylation pathway may contribute to the development of lung injury and fibrosis, and that blocking this phosphorylation ¡V a regulatory mechanism in which proteins and receptors are switched on or off ¡V improved Bleomycin-induced lung fibrosis in mice. The study appears on-line October 5 in Proceedings of the Library of Science (PloS ONE).
Bleomycin is a common chemotherapy drug used to treat many forms of cancer, according to study authors Martina Buck, PhD, associate professor of medicine, and Mario Chojkier, MD, professor of medicine, both researchers at UC San Diego Moores Cancer Center and the VA San Diego Healthcare System. ¡§Unfortunately, use of Bleomycin has damaging side effects, including lung fibrosis. We are hopeful that this discovery could provide a way to stop such lung damage so that cancer patients could better tolerate this chemotherapy,¡¨ said Buck.
The downstream molecular mechanism that causes Bleomycin-induced lung fibrosis remained unknown. The scientists set out to identify the specific signaling involving a single amino acid within a specific domain of one protein that could be blocked the half the progression of such injury, in order to design effective targeted therapeutics.
They found that blocking RSK phosphorylation of a binding protein called C/EBP-Beta on the RSK macromolecule Thr217 with either a single point mutation or a blocking peptide ameliorated the progression of lung injury and fibrosis induced by Bleomycin in mice.
¡§We hypothesized that this pathway was critical given similarities between liver and lung fibrogenesis. RSK plays an important role in both the macrophage inflammatory function and survival of activated liver myofibroblasts ¡V cells that contribute to maintenance and tissue metabolism,¡¨ said Buck. ¡§Therefore, we proposed that a similar signaling mechanism is also responsible for lung injury and fibrosis.¡¨
By identifying the peptide that shuts down this process, the researchers were essentially able to sequester a small piece of an important regulatory protein, C/EBP Beta, responsible for fibrosis, thereby stopping phosphorylation. ¡§Basically, the kinase protein gets hung up, trying again and again ¡V unsuccessfully ¡V to ¡¥turn on¡¦ the fibrous growth,¡¨ Buck added.
In addition, phosphorylation of human C/EBP£] was induced inƒnhuman lung fibroblasts in culture and in situ in lungs of patients with severe lung fibrosis, but not in control lungs, suggesting that this signaling pathway may be also relevant in human lung injury and fibrosis.
The researchers add that it is premature to assess whether this pathway will provide an effective therapeutic target. However, blocking progression of lung fibrosis could decrease the need for lung transplantation, since IPF is the main indication for lung transplants worldwide.
The link to the actual article is at:
http://issuu.com/pulmonaryfibrosisfoundation/docs/phosphorylation
http://issuu.com/pulmonaryfibrosisfoundation/docs/phosphorylation
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Bioengineering Lungs for Transplantation
By Dr. Daniel Dilling, FCCP
Lung transplantation, at one time, seemed like science fiction, but innovations in surgical technique and immunosuppression made it clinical reality. Limited supply of donor lungs and the vagaries of immunosuppression still limit its success.
A pair of articles published last year has created an aura of science fiction once again (Ott et al. Nat Med. 2010;16[8]:927; Petersen et al. Science. 2010;329[5991]:538). Two groups of researchers developed an engineered lung through decellularization and recellularization in a rat model. In the experiments, an explanted adult rat lung was decellularized with a detergent, creating a sort of scaffolding of the lung. It retained its ultrastructural properties with complete removal of antigenic cellular components. Preservation of lung architecture and microvasculature was seen on CT imaging. Even the alveolar septal architecture remained undisturbed.
This acellular matrix was mounted inside a biomimetic bioreactor, where fetal vascular endothelium could be seeded into the pulmonary artery and fetal pulmonary epithelium into the trachea. Inside the bioreactor, the lungs were perfused with blood and ventilated at physiologic pressures, with gas exchange comparable to native lungs under the same conditions. After 4 to 8 days of culture, the lungs were removed and successfully implanted into syngeneic rats where selective blood gas analysis demonstrated gas exchange in the engineered lungs.
Tissue-engineered lungs could alleviate donor availability and many of the allo-immunity problems, if such a concept could be developed to clinical reality. There are many hurdles to overcome, but along with other novel concepts, such as a microchip that performs gas exchange (Science. 2010 Jun 25; 328(5986):1662), we must wonder what the future holds for such technologies.
One of the lead researchers, Dr. Tom Peterson, will discuss the topic, "Tissue-Engineered Lungs for In Vivo Implantation" at the Transplant NetWork open meeting on Monday, October 24, at 7:15 am in the Honolulu Convention Center, room 318B.
Lung transplantation, at one time, seemed like science fiction, but innovations in surgical technique and immunosuppression made it clinical reality. Limited supply of donor lungs and the vagaries of immunosuppression still limit its success.
A pair of articles published last year has created an aura of science fiction once again (Ott et al. Nat Med. 2010;16[8]:927; Petersen et al. Science. 2010;329[5991]:538). Two groups of researchers developed an engineered lung through decellularization and recellularization in a rat model. In the experiments, an explanted adult rat lung was decellularized with a detergent, creating a sort of scaffolding of the lung. It retained its ultrastructural properties with complete removal of antigenic cellular components. Preservation of lung architecture and microvasculature was seen on CT imaging. Even the alveolar septal architecture remained undisturbed.
This acellular matrix was mounted inside a biomimetic bioreactor, where fetal vascular endothelium could be seeded into the pulmonary artery and fetal pulmonary epithelium into the trachea. Inside the bioreactor, the lungs were perfused with blood and ventilated at physiologic pressures, with gas exchange comparable to native lungs under the same conditions. After 4 to 8 days of culture, the lungs were removed and successfully implanted into syngeneic rats where selective blood gas analysis demonstrated gas exchange in the engineered lungs.
Tissue-engineered lungs could alleviate donor availability and many of the allo-immunity problems, if such a concept could be developed to clinical reality. There are many hurdles to overcome, but along with other novel concepts, such as a microchip that performs gas exchange (Science. 2010 Jun 25; 328(5986):1662), we must wonder what the future holds for such technologies.
One of the lead researchers, Dr. Tom Peterson, will discuss the topic, "Tissue-Engineered Lungs for In Vivo Implantation" at the Transplant NetWork open meeting on Monday, October 24, at 7:15 am in the Honolulu Convention Center, room 318B.
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