Imaging of cardiac fibroblast activation in a patient after acute myocardial infarction using 68Ga-FAPI-04.

Our previous study has demonstrated the feasibility of noninvasive imaging of fibroblast activation protein (FAP)-expression after myocardial infarction (MI) in MI-territory in a rat model with 68Ga-FAPI-04-PET. In the current extended clinical case, we sought to delineate cardiac uptake of 68Ga-FAPI-04 in a patient after MI with clinical indication for the evidence of fibroblast activation. Carcinoma patients without cardiac disease underwent 68Ga-FAPI-04-PET/CT as control. The patient with one-vessel disease underwent dynamic 68Ga-FAPI-04-cardiac-PET/CMR for 60 minutes. Correlation of cardiac 68Ga-FAPI-04 uptake with clinical findings, ECG, echocardiography, coronary-arteriography and enhanced cardiac-MRI with T1 MOLLI and ECV mapping were performed. No uptake was found in normal myocardium and in mature scar. A focal intense 68Ga-FAPI-04 uptake with continuous wash-out in the infarct territory of coronary occlusion correlating with T1 and ECV mapping was observed. The uptake of 68Ga-FAPI-04 extends beyond the actual infarcted area and overestimates the infarct size as confirmed by follow-up CMR.

Patient-Reported and Magnetic Resonance Imaging Outcomes of Third-Generation Autologous Chondrocyte Implantation After 10 Years.

PURPOSE: To evaluate the long-term clinical and radiologic outcomes of third-generation autologous chondrocyte implantation (ACI) for the treatment of focal cartilage defects of the knee. METHODS: Data capture was carried out between 2004 and 2018. Included were patients with cartilage defects of the knee joint with an International Cartilage Repair Society grade of III or higher treated with third-generation ACI who had a minimum follow-up period of 10 years. International Knee Documentation Committee scores and assessment of pain at rest and on movement using visual analog scale scores were captured preoperatively and at 6 months postoperatively, as well as annually thereafter. In addition, we performed magnetic resonance imaging examinations in 13 cases after 10 years. The MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score was used to evaluate the ACI cartilage. RESULTS: A total of 54 patients met the inclusion criteria. Of these, 30 reached the 10-year follow-up point and were included in this assessment. At 10 years postoperatively, all clinical outcome parameters showed a statistically significant improvement compared with the preoperative situation, with a responder rate of 70%. The average MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score after 10 years was 59.2 points (range, 20-100 points), and over 60% of the evaluated patients showed good integration of the implant at 10 years postoperatively. CONCLUSIONS: The clinical and radiologic findings of this study show that third-generation ACI is a suitable and effective option in the treatment of full-thickness cartilage defects of the knee. At 10 years after surgery, third-generation ACI shows stable results and leads to significant improvement in all clinical outcome parameters. Despite these results, revision surgery after third-generation ACI is common and was needed in 23% of patients in this study. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Evolution of patency rates of self-expandable bare metal stents for endovascular treatment of femoro-popliteal arterial occlusive disease: Does stent design matter?

OBJECTIVE: To analyse the patency rates of femoro-popliteal stenting with different self-expandable Nitinol stent-designs. METHODS: Two hundred and twenty-two patients (142 (64%) male; age 72.4 ± 11.6 years) with symptomatic femoro-popliteal peripheral arterial occlusive disease (PAOD) underwent percutaneous transluminal angioplasty (PTA) and stenting with three different Nitinol stents (interwoven IW: n = 70; closed-cell CC: n = 85; open-cell OC: n = 67). One-year post-procedural target lesion revascularization (TLR_12M) rates were investigated with regard to co-morbidities: diabetes (DBM), hyperlipidaemia (HLP), hypertension (RR), coronary artery disease (CAD) and degree of calcification. RESULTS: Twelve-month follow-up data were available for 60, 69 and 50 patients in the IW, OC and CC groups (179 patients in total). The cumulative patency (IW: 52 (86.7%); OC: 50 (72.5%); CC: 23 (46.0%); P < 0.001) and the TLR_12M rates (IW: 8 (13.3%); OC: 19 (27.5%); CC: 27 (54.0%); P < 0.001) differed significantly, as did the subgroup analyses (DBM: P = 0.05; RR: P = 0.003; HLP: P = 0.005; CAD: P = 0.02; localization: P < 0.001; calcification: P < 0.001), with the best patency for the IW stent and the highest TLR_12M for the CC stent. CONCLUSION: The interwoven stent-design was superior to the standard open- and closed-cell stent-designs in endovascular treatment of femoro-popliteal PAOD in a follow-up period of 12 months. KEY POINTS: • Results of femoro-popliteal stenting are still unsatisfactory. • Comparative studies for currently available different Nitinol stent-designs are lacking. • This is a first comparative study on long-term patency of different Nitinol stent-designs. • Interwoven stent-design leads to improved long-term patency. • Interwoven stent-design leads to lower TLR than other stent-designs.

Submillisievert Computed Tomography of the Chest Using Model-Based Iterative Algorithm: Optimization of Tube Voltage With Regard to Patient Size.

OBJECTIVE: The aim of this study was to define optimal tube potential for soft tissue and vessel visualization in dose-reduced chest CT protocols using model-based iterative algorithm in average and overweight patients. METHODS: Thirty-six patients receiving chest CT according to 3 protocols (120 kVp/noise index [NI], 60; 100 kVp/NI, 65; 80 kVp/NI, 70) were included in this prospective study, approved by the ethics committee. Patients' physical parameters and dose descriptors were recorded. Images were reconstructed with model-based algorithm. Two radiologists evaluated image quality and lesion conspicuity; the protocols were intraindividually compared with preceding control CT reconstructed with statistical algorithm (120 kVp/NI, 20). Mean and standard deviation of attenuation of the muscle and fat tissues and signal-to-noise ratio of the aorta were measured. RESULTS: Diagnostic images (lesion conspicuity, 95%-100%) were acquired in average and overweight patients at 1.34, 1.02, and 1.08 mGy and at 3.41, 3.20, and 2.88 mGy at 120, 100, and 80 kVp, respectively. Data are given as CT dose index volume values. CONCLUSIONS: Model-based algorithm allows for submillisievert chest CT in average patients; the use of 100 kVp is recommended.

Cell surface engineering using glycosylphosphatidylinositol anchored tissue inhibitor of matrix metalloproteinase-1 stimulates cutaneous wound healing.

The balance between matrix metalloproteinases and their endogenous tissue inhibitors (TIMPs) is an important component in effective wound healing. The biologic action of these proteins is linked in part to the stoichiometry of TIMP/matrix metalloproteinases/surface protein interactions. We recently described the effect of a glycosylphosphatidylinositol (GPI) anchored version of TIMP-1 on dermal fibroblast biology. Here, cell proliferation assays, in vitro wound healing, electrical wound, and impedance measurements were used to characterize effects of TIMP-1-GPI treatment on primary human epidermal keratinocytes. TIMP-1-GPI stimulated keratinocyte proliferation, as well as mobilization and migration. In parallel, it suppressed the migration and matrix secretion of dermal myofibroblasts, and reduced their secretion of active TGF-ß1. Topical application of TIMP-1-GPI in an in vivo excisional wound model increased the rate of wound healing. The agent positively influenced different aspects of wound healing depending on the cell type studied. TIMP-1-GPI counters potential negative effects of overactive myofibroblasts and enhances the mobilization and proliferation of keratinocytes essential for effective wound healing. The application of TIMP-1-GPI represents a novel and practical clinical solution for facilitating healing of difficult wounds.

Aortic Vascular Graft and Endograft Infection-Patient Outcome Cannot Be Determined Based on Pre-Operative Characteristics.

Vascular graft/endograft infection (VGEI) is a serious complication after aortic surgery. This study investigates VGEI and patient characteristics, PET/CT quantification before surgical or conservative management of VGEI and post-intervention outcomes in order to identify patients who might benefit from such a procedure. PET standard uptake values (SUV) were quantitatively assessed and compared to a non-VGEI cohort. The primary endpoints were in-hospital mortality and aortic reintervention-free survival at six months. Ninety-three patients (75% male, 65 ± 10 years, 82% operated) were included. The initial operation was mainly for aneurysm (67.7%: 31% EVAR, 12% TEVAR, 57% open aortic repair). Thirty-two patients presented with fistulae. PET SUVTLR (target-to-liver ratio) showed 94% sensitivity and 89% specificity. Replacement included silver-coated Dacron (21.3%), pericardium (61.3%) and femoral vein (17.3%), yet the material did not influence the overall survival (p = 0.745). In-hospital mortality did not differ between operative and conservative treatment (19.7% vs. 17.6%, p = 0.84). At six months, 50% of the operated cohort survived without aortic reintervention. Short- and midterm morbidity and mortality remained high after aortic graft removal. Neither preoperative characteristics nor the material used for reconstruction influenced the overall survival, and, with limitations, both the in-hospital and midterm survival were similar between the surgically and conservatively managed patients.

Novel Discovery of the Somatostatin Receptor (SSTR2) in Pleomorphic Adenomas via Immunohistochemical Analysis of Tumors of the Salivary Glands.

Reliable preoperative diagnosis between salivary gland tumor entities is difficult. In this monocentric retrospective study, we examined the somatostatin receptor 2 (SSTR2) status of salivary gland tumors after salivary gland tumor resection via immunohistochemistry (IHC), and stains were compared in analogy to the HER2 mamma scale. A total of 42.3% of all pleomorphic adenoma (PA) tumors (42 of 99, 95% confidence interval 32.5-52.8%) demonstrated ≥20% of cells displaying the SSTR2 as compared to just 1% of all other tumors (1/160, 95% CI 0.02-3.4%). The other tumor was a neuroendocrine carcinoma. PA had a higher intensity of SSTR2 staining, with 90.9% staining ≥ an intensity of 2 (moderate). Tumors with an intensity of SSTR2 expression equal to or greater than 2 had an 89.9% likelihood of being a PA (95% CI: 82.2-95.0%, AUC: 0.928). Only one Warthin tumor demonstrated a 'strong' SSTR2 staining intensity. No Warthin tumor showed a percentage of cells staining for SSTR2 above ≥20%. This result demonstrates consistent and strong expression of SSTR2 in PAs as compared to Warthin tumors, which may allow physicians to utilize radioligand-somatostatin analog PET CT/MR imaging to diagnose the PA. SSTR2 positivity, if shown to be clinically relevant, may allow peptide receptor radionuclide therapy in the future.

Quantitative differentiation of minimal-fat angiomyolipomas from renal cell carcinomas using grating-based x-ray phase-contrast computed tomography: An ex vivo study.

BACKGROUND: The differentiation of minimal-fat-or low-fat-angiomyolipomas from other renal lesions is clinically challenging in conventional computed tomography. In this work, we have assessed the potential of grating-based x-ray phase-contrast computed tomography (GBPC-CT) for visualization and quantitative differentiation of minimal-fat angiomyolipomas (mfAMLs) and oncocytomas from renal cell carcinomas (RCCs) on ex vivo renal samples. MATERIALS AND METHODS: Laboratory GBPC-CT was performed at 40 kVp on 28 ex vivo kidney specimens including five angiomyolipomas with three minimal-fat (mfAMLs) and two high-fat (hfAMLs) subtypes as well as three oncocytomas and 20 RCCs with eight clear cell (ccRCCs), seven papillary (pRCCs) and five chromophobe RCC (chrRCC) subtypes. Quantitative values of conventional Hounsfield units (HU) and phase-contrast Hounsfield units (HUp) were determined and histogram analysis was performed on GBPC-CT and grating-based attenuation-contrast computed tomography (GBAC-CT) slices for each specimen. For comparison, the same specimens were imaged at a 3T magnetic resonance imaging (MRI) scanner. RESULTS: We have successfully matched GBPC-CT images with clinical MRI and histology, as GBPC-CT presented with increased soft tissue contrast compared to absorption-based images. GBPC-CT images revealed a qualitative and quantitative difference between mfAML samples (58±4 HUp) and oncocytomas (44±10 HUp, p = 0.057) and RCCs (ccRCCs: 40±12 HUp, p = 0.012; pRCCs: 43±9 HUp, p = 0.017; chrRCCs: 40±7 HUp, p = 0.057) in contrast to corresponding laboratory attenuation-contrast CT and clinical MRI, although not all differences were statistically significant. Due to the heterogeneity and lower signal of oncocytomas, quantitative differentiation of the samples based on HUp or in combination with HUs was not possible. CONCLUSIONS: GBPC-CT allows quantitative differentiation of minimal-fat angiomyolipomas from pRCCs and ccRCCs in contrast to absorption-based imaging and clinical MRI.

Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF- ß 1 activation and reduces regulatory ID gene expression.

Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix metalloproteinase activity through 1:1stoichiometric binding. Human TIMP-1 fused to a glycosylphosphatidylinositol(GPI) anchor (TIMP-1 - GPI) shifts the activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1 - GPI treated renal cell carcinoma cells show increased apoptosis and reduced proliferation.Transcriptomic profiling and regulatory pathway mapping were used to identify the potential mechanisms driving these effects. Significant changes in the DNA binding inhibitors, TGF- ß 1/SMAD and BMP pathways resulted from TIMP-1 - GPI treatment. These events were linked to reduced TGF- ß 1 signaling mediated by inhibition of proteolytic processing of latent TGF- ß 1 by TIMP-1 - GPI.

Temporary Reactive Response of Axillary Lymph Nodes to COVID-19 Vaccination on 18F-rhPSMA-7.3 PET/CT in Patients with Prostate Cancer.

Vaccine-associated lymphadenopathy (VAL) is a common finding on 18F-FDG PET/CT examinations after coronavirus disease 2019 (COVID-19) vaccination. However, data regarding VAL on 18F-rhPSMA-7.3-ligand PET are currently lacking. This study assesses the prevalence, temporal response to vaccination, and characteristics of VAL. Methods: Two hundred thirty-three consecutive vaccinated and 41 unvaccinated patients with confirmed prostate cancer who underwent 18F-rhPSMA-7.3 PET/CT were retrospectively analyzed. Size and uptake of the axillary lymph nodes were measured. Ratios of SUVmax of ipsilateral to contralateral axillary lymph node (SUVratio) were determined. The characteristics of SUVratio in respect to the duration of PSMA avidity in the axillary lymph node after COVID-19 vaccination was analyzed. Results: The prevalence of VAL on 18F-rhPSMA-7.3 PET was 45%. Up to a period of 8 wk after the last COVID-19 vaccination, SUVratio was positive (2.05 ± 0.17). Thereafter, SUVratio dropped significantly (1.35 ± 0.09) and approached the value of unvaccinated group (1.1 ± 0.2). SUVratio of metastatic axillary lymph nodes was very high (>11) and can be easily detected visually or semiquantitatively. In 3 patients, we observed suspected development and consecutively confirmed involving metastasis of axillary lymph node with SUVratio between 4.0 to 6.6. Correlation between SUVratio and lymph node size (r = 0.93, P < 0.0001) and lymph node size and duration after vaccine (r = -0.88, P < 0.0008) was found. Conclusion: Increased uptake of the PSMA ligand 18F-rhPSMA-7.3 by axillary lymph nodes is common after COVID-19 vaccination and can persist for 8 wk. This finding should be considered in the interpretation of 18F-rhPSMA-7.3 PET/CT examinations.

Advances in multiscale image processing and its effects on image quality in skeletal radiography.

Multi-frequency processing (MFP) leads to enhanced image quality (IQ) of radiographs. This study is to determine the effect of third generation MFP (M3) on IQ in comparison to standard second-generation MFP (M2). 20 cadavers were examined and post-processing of radiographs was performed with both M2 and M3. Three readers blinded to the MFP used for each image independently compared corresponding image pairs according to overall IQ and depiction of bony structures and soft tissue (+ 2: notably better > 0: equal > - 2: notably worse). A significant deviation of the median grade from grade 0 (equal) (p < 0.01) for each evaluator A, B and C speaks against an equal image quality of M2- and M3-images. M3-images were categorized with better grades (+ 1, + 2) in 87.7% for overall image quality, in 90.4% for soft tissue and 81.8% for bony structures. M3 images showed significant higher averaged SNR and CNR for all investigated lower extremities than that of M2 images (0.031 < p < 0.049). The newest generation of MFP leads to significantly better depiction of anatomical structures and overall image quality than in images processed with the preceding generation of MFP. This provides increased diagnostic accuracy and further decreased radiation exposure.

Imaging characteristics of intravascular spherical contrast agents for grating-based x-ray dark-field imaging - effects of concentrations, spherical sizes and applied voltage.

This study investigates the x-ray scattering characteristics of microsphere particles in x-ray-grating-based interferometric imaging at different concentrations, bubble sizes and tube voltages (kV). Attenuation (ATI), dark-field (DFI) and phase-contrast (PCI) images were acquired. Signal-to-noise (SNR) and contrast-to-noise ratios with water (CNRw) and air as reference (CNRa) were determined. In all modalities, a linear relationship between SNR and microbubbles concentration, respectively, microsphere size was found. A significant gain of SNR was found when varying kV. SNR was significantly higher in DFI and PCI than ATI. The highest gain of SNR was shown at 60 kV for all media in ATI and DFI, at 80 kV for PCI. SNR for all media was significantly higher compared to air and was slightly lower compared to water. A linear relationship was found between CNRa, CNRw, concentration and size. With increasing concentration and decreasing size, CNRa and CNRw increased in DFI, but decreased in PCI. Best CNRa and CNRw was found at specific combination of kV and concentration/size. Highest average CNRa and CNRw was found for microspheres in ATI and PCI, for microbubbles in DFI. Microspheres are a promising contrast-media for grating-based-interferometry, if kV, microsphere size and concentration are appropriately combined.

Imaging of hip and thigh muscle injury: a pictorial review.

Muscle injuries of the hip and thigh are a highly relevant issue in competitive sports imaging. The gold standard in diagnostic imaging of muscle injuries is magnetic resonance imaging (MRI). Radiologists need to be familiar with typical MRI findings in order to accurately detect and classify muscle injuries. Proper interpretation of the findings is crucial, especially in elite athletes. In soccer players, muscle injuries of the hip and thigh are the most common reason for missing a game.The present pictorial review deals with the diagnostic assessment, especially MRI, of muscle injuries of the hip and thigh. Typical MR findings in muscle injuries include edema, hematoma, and tendinous avulsion as well as partial or complete muscle tear. To estimate the time to return to play, a grading into three groups-muscle strain, partial tear, complete tear-has traditionally been used. Taking into account the most recent literature, there are other prognostic factors such as the longitudinal length of a tear, the tendon's intramuscular component, or persisting edema.

Qualitative and Quantitative Evaluation of Structural Myocardial Alterations by Grating-Based Phase-Contrast Computed Tomography.

OBJECTIVES: Grating-based phase-contrast computed tomography (gb-PCCT) relies on x-ray refraction instead of absorption to generate high-contrast images in biological soft tissue. The aim of this study was to evaluate the potential of gb-PCCT for the depiction of structural changes in heart disease. MATERIALS AND METHODS: Four human heart specimens from patients with hypertensive disease, ischemic disease, dilated heart disease, and cardiac lipomatosis were examined. The gb-PCCT setup consisted of an x-ray tube (40 kV, 70 mA), grating-interferometer, and detector, and allowed simultaneous acquisition of phase- and absorption-contrast data. With histopathology as the standard of reference, myocardium (MC), fibrotic scar (FS), interstitial fibrosis (IF), and fatty tissue (FT) were visually and quantitatively evaluated. Systematic differences in absorption- and phase-contrast Hounsfield units (HUabs and HUp) were assessed. RESULTS: Thirteen corresponding cross-sections were included, and MC, FS, IF, and FT were found in 13 (100%), 4 (30.8%), 7 (53.8%), and 13 (100%) cross-sections, respectively. Mean HUp/HUabs were 52.5/54.1, 86.6/69.7, 62.4/62.3, and -38.6/-258.9 for MC, FS, IF, and FT, respectively. An overlap in HUabs was observed for MC and IF (P = 0.84) but not for HUp (P < 0.01). Contrast-to-noise ratios were significantly higher in phase- than in absorption-contrast for MC/FT (35.4 vs 7.8; P < 0.01) and for MC/FS (12.3 vs 0.2; P < 0.01). CONCLUSIONS: Given its superior soft tissue contrast, gb-PCCT is able to depict structural changes in different cardiomyopathies, which can currently not be obtained by x-ray absorption-based imaging methods. If current technical limitations can be overcome, gb-PCCT may evolve as a powerful tool for the anatomical assessment of cardiomyopathy.

Dark-field imaging in coronary atherosclerosis.

OBJECTIVES: Dark-field imaging based on small angle X-ray scattering has been shown to be highly sensitive for microcalcifications, e.g. in breast tissue. We hypothesized (i) that high signal areas in dark-field imaging of atherosclerotic plaque are associated with microcalcifications and (ii) that dark-field imaging is more sensitive for microcalcifications than attenuation-based imaging. METHODS: Fifteen coronary artery specimens were examined at an experimental set-up consisting of X-ray tube (40kV), grating-interferometer and detector. Tomographic dark-field-, attenuation-, and phase-contrast data were simultaneously acquired. Histopathology served as standard of reference. To explore the potential of dark field imaging in a full-body CT system, simulations were carried out with spherical calcifications of different sizes to simulate small and intermediate microcalcifications. RESULTS: Microcalcifications were present in 10/10 (100%) cross-sections with high dark-field signal and without evidence of calcifications in attenuation- or phase contrast. In positive controls with high signal areas in all three modalities, 10/10 (100%) cross-sections showed macrocalcifications. In negative controls without high signal areas, no calcifications were detected. Simulations showed that the microcalcifications generate substantially higher dark-field than attenuation signal. CONCLUSIONS: Dark-field imaging is highly sensitive for microcalcifications in coronary atherosclerotic plaque and might provide complementary information in the assessment of plaque instability.

Qualitative and Quantitative Imaging Evaluation of Renal Cell Carcinoma Subtypes with Grating-based X-ray Phase-contrast CT.

Current clinical imaging methods face limitations in the detection and correct characterization of different subtypes of renal cell carcinoma (RCC), while these are important for therapy and prognosis. The present study evaluates the potential of grating-based X-ray phase-contrast computed tomography (gbPC-CT) for visualization and characterization of human RCC subtypes. The imaging results for 23 ex vivo formalin-fixed human kidney specimens obtained with phase-contrast CT were compared to the results of the absorption-based CT (gbCT), clinical CT and a 3T MRI and validated using histology. Regions of interest were placed on each specimen for quantitative evaluation. Qualitative and quantitative gbPC-CT imaging could significantly discriminate between normal kidney cortex (54 ± 4 HUp) and clear cell (42 ± 10), papillary (43 ± 6) and chromophobe RCCs (39 ± 7), p < 0.05 respectively. The sensitivity for detection of tumor areas was 100%, 50% and 40% for gbPC-CT, gbCT and clinical CT, respectively. RCC architecture like fibrous strands, pseudocapsules, necrosis or hyalinization was depicted clearly in gbPC-CT and was not equally well visualized in gbCT, clinical CT and MRI. The results show that gbPC-CT enables improved discrimination of normal kidney parenchyma and tumorous tissues as well as different soft-tissue components of RCCs without the use of contrast media.

Treatment of dermal fibroblasts with GPI-anchored human TIMP-1 protein moderates processes linked to scar formation.

Tissue inhibitors of metalloproteinases exhibit diverse physiological/biological functions including moderation of the proteolytic processing of growth factors and turnover of extracellular matrix. These various biological activities are linked in part to the stoichiometry of tissue inhibitor of metalloprotein/matrix metalloprotein (TIMP/MMP)/surface protein interactions. TIMP-1, a secreted protein, can be detected on the cell surface only through its interaction with surface-bound proteins. Proteins anchored by glycosylphosphatidylinositol (GPI), when purified and added to cells or tissues, are efficiently incorporated into their surface membranes. A GPI anchor was fused to TIMP-1 to focus defined concentrations of the inhibitory protein independently on the surface of primary dermal fibroblast cells. Exogenously added recombinant TIMP-1-GPI effectively inserted into the cell membrane of fibroblasts blocked the secretion of MMPs and markedly altered the stoichiometry of MMP association with the cell surface. TIMP-1-GPI treatment resulted in inhibition of fibroblast-reduced proliferation, and transiently reduced expression of fibrosis-associated genes. These effects were dose dependent. Treated cells also showed a more proapoptotic phenotype based on apoptotic assays and western blot analysis for apoptosis-associated protein expression. GPI-anchored TIMP-1 may represent a more effective version of the protein for use in therapeutic approaches to help control fibrosis and scar formation.

Recombinant GPI-anchored TIMP-1 stimulates growth and migration of peritoneal mesothelial cells.

BACKGROUND: Mesothelial cells are critical in the pathogenesis of post-surgical intraabdominal adhesions as well as in the deterioration of the peritoneal membrane associated with long-term peritoneal dialysis. Mesothelial denudation is a pathophysiolocigally important finding in these processes. Matrix metalloproteinase (MMP) biology underlies aspects of mesothelial homeostasis as well as wound repair. The endogenous tissue inhibitors of metalloproteinases (TIMPs) moderate MMP activity. METHODS AND FINDING: By modifying human TIMP-1 through the addition of a glycosylphosphatidylinositol (GPI) anchor, a recombinant protein was generated that efficiently focuses TIMP-1 on the cell surface. Treatment of primary mesothelial cells with TIMP-1-GPI facilitates their mobilization and migration leading to a dramatic increase in the rate of wound experimental closure. Mesothelial cells treated with TIMP-1-GPI showed a dose dependent increase in cell proliferation, reduced secretion of MMP-2, MMP-9, TNF-α and urokinase-type plasminogen activator (uPA), but increased tissue plasminogen activator (t-PA). Treatment resulted in reduced expression and processing of latent TGF-ß1. CONCLUSIONS: TIMP-1-GPI stimulated rapid and efficient in vitro wound closure. The agent enhanced mesothelial cell proliferation and migration and was bioactive in the nanogram range. The application of TIMP-1-GPI may represent a new approach for limiting or repairing damaged mesothelium.