Considering the nearly universal skepticism transmyocardial laser revascularization (TMLR) aroused a few years ago, the so-called snake heart procedure has come a long way. The notion that the human heart enjoys significant perfusion from a spongy underlay of microcapillaries and sinusoids has been embraced by hundreds of researchers who have poked away at the coronary bed with external and internal lasers, radiofrequency probes, rotary cutters and saline jets, as well as developing technologies for implanting angiogenic growth factors into and around the resultant channels. TMLR has been described as a therapeutic option for end-stage coronary artery disease when percutaneous transluminal angioplasty and surgical myocardial revascularization are no longer possible and transplantation is not indicated. While debate continues to rage among surgeons and interventionists over the best way to perform transmyocardial laser, a greater question looms over the field: how does it work? No one has been able to explain yet why the procedure works in some patients and utterly fails in others, or to convincingly substantiate the procedure’s contributions to myocardial reperfusion. A few investigators believe that the procedure’s secret lies in creating patent channels. However, mid- and long-term patency of laser-created channels seem not to be required for successful treatment as initially assumed. The development of new vessels within and around the scar following TMLR (a phenomenon called ‘neoangiogenesis’) has moved more and more to the center of attention during the last few years. Some form of angiogenesis or neovascularization around the channels is the most favored explanation now, but nobody knows how TMLR stimulates such processes or how to measure them effectively. Although prospective randomized studies have been able to demonstrate some effectiveness of this treatment, the exact mechanisms of laser revascularization are still not completely elucidated. The notion of mechanisms such as sympathetic myocardial denervation and induction of microinfarctions transforming ischemia into necrotic myocardium has been abandoned. As recently as 1996, the prospect of transmyocardial revascularization becoming a breakthrough therapy seemed exciting enough to the financial market that the stock of PLC Medical Systems, then the front-runner in the field, soared to USD 32 per share. But in only the 2nd year since receiving FDA approval, the company is now trading at around USD 1.5 a share and the laser sales have fallen below expectations. One problem may be that many hospitals do not switch on their TMLR lasers very often once they are installed, with usage estimates as low as one or two procedures per month in some centers.
BACKGROUND: Several mouse lung transplantation (Tx) models have been proposed for the study of chronic airway fibrosis (CAF), the most prevalent complication seen in human lung transplant recipients, termed chronic lung allograft dysfunction (CLAD). Alternatively, it has been called for to establish an experimental animal model for restrictive allograft syndrome (RAS), another phenotype of CLAD. However, these mouse transplant models exhibit significant heterogeneity in consistency and re-producibility. We therefore aimed at reevaluating current available models. METHODS: 4 different Tx combinations were employed that manifest CAF: 2 minor antigen-mismatched Tx combinations (MINOR, donor: C57BL/10, recipient: C57BL/6J); or MINOR-N using recipient C57BL/6N, major histocompati-bility antigen-mismatched immunosuppressed Tx (MAJOR, donor: BALB/c, recipient: C57BL/6J) and syngeneic Tx (SYN, donor and recipient: C57BL/6J) as control. The recipients were harvested and analyzed at week 8. Oxygenation, histology, reverse transcription polymerase chain reaction (RT-PCR), and magnetic resonance imaging were performed to analyze outcome of those models. RESULTS: The most prominent manifestation of CAF, thickest subepithelial fibrotic changes, worst oxygenation and the most severe acute rejection were detected in the MAJOR group, compared to all other (p<0.05). Gene expressions of TNF-ï¿¿ and TGF-ï¿¿1 were higher, and IL-10 was lower in the MAJOR group. Im-munohistochemistry found pleuroparenchymal fibrotic change in both the MAJOR and MINOR-J group. CONCLUSIONS: We propose the major mismatch model under mild immunosuppression as the most suitable model for studying posttransplant CAF, and both the major and minor mismatch models for the restrictive phenotype. Wolfgang (2018). Chronic airway fibrosis in orthotopic mouse lung transplantation models: an experimental reappraisal. Transplantation, 102(2):e49-e58.
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