Impact of antiviral therapy on short- and long-term outcomes of patients with chronic obstructive pulmonary disease after influenza infection.

Background: Respiratory complications often accompany influenza in patients with chronic obstructive pulmonary disease (COPD). In this retrospective study, we quantified the impact of antiviral therapy on exacerbations, healthcare resource utilization (HRU), and costs in patients with COPD across 5 influenza seasons. Methods: Using claims data from US MarketScan® databases, we identified patients with COPD who had an influenza diagnosis during the 2012-2016 influenza seasons. Patients who received a neuraminidase inhibitor within 48 h of diagnosis (N = 4134) were identified and propensity score-matched 1:1 to a comparator cohort of untreated patients. We determined COPD- and pneumonia-related HRU and costs during month 1, each subsequent quarter, and months 2-13. Results: Antiviral-treated patients had a significantly lower frequency of COPD-related outcomes than untreated patients during all periods (exacerbations: 10.4% vs 18.2% [month 1] and 17.7% vs 24.2% [months 2-13]; inpatient visit: 2.5% vs 7.9% [month 1] and 3.8% vs 6.7% [months 2-13]; P < 0.0001, all comparisons). Treated patients also had significantly lower outpatient and emergency department (ED) visits beyond month 1. Pneumonia-related inpatient, ED, and outpatient visits were significantly lower in antiviral-treated patients than in untreated patients over all periods (P < 0.0001, all comparisons). In all HRU categories, COPD- and pneumonia-related costs were significantly lower in treated patients over all periods (month-1 ED visit costs were higher). Conclusions: Antiviral treatment in patients with COPD and influenza is associated with significantly lower HRU and costs in the postinfection month and for an entire year following infection compared with untreated patients.

Outcomes of antiviral treatment for influenza in type 2 diabetes.

OBJECTIVES: To evaluate the long-term effects of antiviral treatment on influenza-related health care resource utilization (HCRU) and costs in patients with type 2 diabetes (T2D) and a diagnosis of influenza. STUDY DESIGN: Retrospective cohort study. METHODS: Claims data from the IBM MarketScan Commercial Claims Database were used to identify patients with T2D and a diagnosis of influenza between October 1, 2016, and April 30, 2017. Patients who received antiviral treatment within 2 days of influenza diagnosis were identified and propensity score-matched 1:1 with a comparator cohort of untreated patients. HCRU (number of outpatient visits, emergency department visits, hospitalizations, and duration of hospitalization) and costs were assessed over 1 full year and over each quarter after influenza diagnosis. RESULTS: Treated and untreated matched cohorts consisted of 2459 patients each. In the treated cohort vs the untreated cohort, emergency department visits were reduced 24.6% over 1 year after influenza diagnosis (mean [SD], 0.94 [1.76] vs 1.24 [2.47] visits; P < .0001) and were also reduced significantly during each quarter; the duration of hospitalization decreased 35.6% in the treated cohort vs the untreated cohort over 1 full year (mean [SD], 0.71 [3.36] vs 1.11 [5.60] days; P < .0023). Mean (SD) total health care costs were 17.68% lower in the treated cohort ($20,212 [$58,627]) than in the untreated cohort ($24,552 [$71,830]) over a whole year following the index influenza visit (P = .0203). CONCLUSIONS: Antiviral treatment in patients with T2D and influenza was associated with significantly lower HCRU and costs over at least 1 year after infection.

Impact of influenza infection on the short- and long-term health of patients with chronic obstructive pulmonary disease.

BACKGROUND: Influenza is a common cause of acute respiratory infection that leads to exacerbation of underlying chronic obstructive pulmonary disease (COPD). To elucidate the short- and long-term effects of influenza in patients with COPD, we examined health care resource utilization (HRU) and costs up to 13 months following influenza infection. METHODS: We conducted a retrospective cohort study using U.S. insurance claims data from MarketScan. Patients with an influenza diagnosis during the 2012-2014 influenza seasons and continuous enrollment in a health plan from 12 months before to 13 months after the index influenza diagnosis were identified and propensity score-matched 1:5 to controls without evidence of influenza. COPD- and pneumonia-related outcomes were assessed over 13 months following influenza diagnosis. RESULTS: COPD-associated outcomes after diagnosis were significantly worse in patients with influenza (n = 7,087) vs. controls (n = 35,435) during the first month (exacerbation: 16.1 vs. 3.4%; outpatient visits: 57.1 vs. 35.2%; emergency department (ED) visits: 10.5 vs. 1.8%; and inpatient visits: 5.6 vs. 0.7%) and months 2-13 (exacerbation: 25.1 vs. 21.1%; outpatient visits: 86.1 vs. 85.8%; ED visits: 20.0 vs. 15.7%; and inpatient visits: 6.5 vs. 5.3%). COPD- and pneumonia-associated costs for months 1 and 2-13 were higher in patients with influenza. LIMITATIONS: The study was subject to a residual imbalance between cohorts despite propensity score matching. The use of diagnostic codes to select patients and identify complications could introduce inaccuracies in estimating events. CONCLUSIONS: HRU and costs were higher in COPD patients with influenza during the first month and over the entire year following infection. This suggests influenza has an impact on respiratory health in patients with COPD that lasts beyond the acute infection.

Prospective, Single-Arm, Longitudinal Study of Biomarkers in Real-World Patients with Severe Asthma.

BACKGROUND: ARIETTA was a prospective, single-arm, noninterventional, multicenter study in patients with severe asthma. OBJECTIVE: To examine the predictive and prognostic abilities of type 2 biomarkers for severe asthma outcomes. METHODS: Adult patients with severe asthma receiving daily inhaled corticosteroids (fluticasone propionate ≥500 µg or equivalent) and ≥1 second controller medication were enrolled. Biomarker, clinical, and safety data were collected over 52 weeks. The primary endpoint was the asthma exacerbation rate over 52 weeks in serum periostin-high (≥50 ng/mL at baseline) versus periostin-low subgroups (<50 ng/mL). Correlations between biomarker levels (periostin, blood eosinophils, IgE, and fractional exhaled nitric oxide [FeNO]) and between central and local laboratory measurements (blood eosinophils and IgE) were assessed. The study was terminated before planned enrollment was completed. RESULTS: Of 465 patients, 66.5% were female, 13.3% were receiving oral corticosteroids, 42.4% had ≥1 exacerbation in the previous year, 52.0% were periostin-high, and 87.5% had type 2 inflammation (blood eosinophils ≥150 cells/µL and/or FeNO ≥25 ppb and/or positive skin allergen test). Biomarker levels correlated poorly with each other. Central and local laboratory blood eosinophil and IgE measurements generally agreed. No difference was observed in exacerbation rates over 52 weeks between periostin-high and periostin-low patients (rate ratio, 0.93; 95% confidence interval, 0.67-1.28; P = .642). Results suggested higher exacerbation rates in patients with blood eosinophils ≥300 cells/µL and FeNO ≥25 ppb. CONCLUSIONS: No prognostic value for serum periostin related to exacerbations was detected. Higher blood eosinophils combined with increased FeNO were potentially associated with increased exacerbation rates.

Assessing biomarkers in a real-world severe asthma study (ARIETTA).

The prognostic value of asthma biomarkers in routine clinical practice is not fully understood. ARIETTA (NCT02537691) is an ongoing, prospective, longitudinal, international, multicentre real-world study designed to assess the relationship between asthma biomarkers and disease-related health outcomes. The trial aims to enrol and follow for 52 weeks approximately 1200 severe asthma patients from approximately 160 sites in more than 20 countries. Severe asthmatics, treated with daily inhaled corticosteroid (≥500 µg of fluticasone propionate or equivalent) and at least 1 second controller medication are to be included. In this real-world study, patients will be treated according to the investigator's routine clinical practices and no treatment regimen will be implemented as part of the trial. At baseline and again at 26 and 52 weeks, FEV1, FeNO, serum periostin, blood eosinophil count and serum IgE will be measured. Asthma-related symptom and quality of life questionnaires will be administered at the visits and during telephone interviews at Weeks 13 and 39. Data about medication use, asthma exacerbation data, asthma-related healthcare utilization and events raising safety concerns will also be collected. This study design, unique in both its scope and scale, will address fundamental unanswered questions regarding asthma biomarkers and their interrelationship, as well as predict deviations in the course of asthma in a real-world setting.

Dipeptidyl peptidase IV (DPPIV/CD26) inhibition does not improve engraftment of unfractionated syngeneic or allogeneic bone marrow after nonmyeloablative conditioning.

In order to develop minimally toxic bone marrow transplantation (BMT) protocols suitable for use in a wider range of indications, it is important to identify ways to enhance BM engraftment at a given level of recipient conditioning. CXCL12/stromal cell-derived factor-1α plays a crucial physiological role in homing of hematopoietic stem cells to BM. It is regulated by the ectopeptidase dipeptidyl peptidase IV (DPPIV; DPP4) known as CD26, which cleaves dipeptides from the N-terminus of polypeptide chains. Blocking DPPIV enzymatic activity had a beneficial effect on hematopoietic stem cell engraftment in various but very specific experimental settings. Here we investigated whether inhibition of DPPIV enzymatic activity through Diprotin A or sitagliptin (Januvia) improves BM engraftment in nonmyeloablative murine models of syngeneic (i.e., CD45-congenic) and allogeneic (i.e., Balb/c to B6) BMT (1 Gy total body irradiation, 10-15 × 10(6) unseparated BM cells/mouse). Neither Diprotin A administered in vivo at the time of BMT and/or used for in vitro pretreatment of BM nor sitagliptin administered in vivo had a detectable effect on the level of multilineage chimerism (follow-up >20 weeks). Similarly, sitagliptin did not enhance chimerism after allogeneic BMT, even though DPPIV enzymatic activity measured in serum was profoundly inhibited (>98% inhibition at peak exposure). Our results provide evidence that DPPIV inhibition via Diprotin A or sitagliptin does not improve engraftment of unseparated BM in a nonmyeloablative BMT setting.

The effect of low-dose Continuous Erythropoietin receptor activator in an experimental model of acute Cyclosporine A induced renal injury.

The use of Cyclosporine A (CsA) as rejection prophylaxis following organ transplantation is limited by its nephrotoxicity. CsA induces renal damage that is associated with tubulo-interstitial injury and parenchymal sequestration of macrophages, perpetuating pro-inflammatory processes. Furthermore, CsA exerts a diabetogenic effect by damaging pancreatic islet cell integrity. Continuous Erythropoietin Receptor Activator (CERA) was shown to mediate tissue-protective and anti-inflammatory effects in various settings of organ injury. Here, we investigated the effect of low dose CERA in a model of CsA-induced renal and pancreatic injury. Rats were exposed to medium-dose CsA for 28 days. Low-dose CERA was given to the treatment group (CERA) (n=6) once per week vs. a CsA-treated control group (CONTROL) (n=6). The effect of CERA on renal and pancreatic injuries was analyzed by organ function, histology, immunohistochemistry (CD68(+)-macrophages, insulin), ELISA (TGF-ß1) and RT-PCR (TGF-ß1, Osteopontin, IL-10). CsA induced functional kidney damage. Low dose CERA did not lead to improved kidney function in the treatment group. However, low dose CERA showed a trend toward upregulation of osteopontin accompanied by increased renal macrophage-infiltration and enhanced parenchymal TGF-ß1 and IL-10 when compared to controls. Moreover, CERA treated animals showed amelioration of pancreatic islet cell injury. In this model of acute CsA-mediated renal injury, low dose CERA administration was associated with anti-inflammatory effects and preservation of pancreatic islet cell viability.

Distribution of macrophages and T cells in syngrafts and allografts after experimental rat lung transplantation.

Macrophages and T cells have a pivotal role in orchestrating the acute lung allograft rejection response. We investigated the spatial and temporal distribution of these immune cells and the synthesis patterns of the T(h)1- and T(h)2-cytokine IL-12 and IL-10 during the early course after transplantation (Tx). Orthotopic single-lung Tx was performed in Lewis to Lewis (syngrafts) and Brown Norway/Lewis F(1) hybrid to Lewis (allografts). Naïve lungs, syngrafts after 5 days and allografts after 3 and 5 days were analyzed for CD68+, CD163+ and CD3+ cells by immunohistochemistry and IL-12 and IL-10 were detected by immunofluorescence. CD68+ macrophages increased in number after allogeneic Tx compared to syngeneic Tx on day 5 (P<.001), CD163+ macrophages sequestrated early around veins (day 3) compared to the accumulation around arteries and bronchioles (P<.001) while CD3+ T cells were scarce. There was a predominance of IL-12 over IL-10 on day 5 after allogeneic Tx (P<.001). CD68+ macrophages were the most abundant cells during acute pulmonary rejection and CD163+ macrophages showed a characteristic distribution pattern over time around vessels and bronchioles. The up-regulation of IL-12 reflects an early response after allo-antigen exposure, indicating a strong impact of the initiation of the T(h)1 pathway at an early phase during acute lung rejection.

Inhibition of CD26/DPP IV attenuates ischemia/reperfusion injury in orthotopic mouse lung transplants: the pivotal role of vasoactive intestinal peptide.

The T cell activation Ag CD26/dipeptidylpeptidase IV (DPP IV) combines co-stimulatory and enzymatic properties. Catalytically, it functions as an exopeptidase, modulating biological activity of key chemokines and peptides. Here we investigated the effect of organ-specific inhibition of DPP IV catalytic activity on ischemia/reperfusion injury after extended ischemia in the mouse model of orthotopic single lung transplantation. C57BL/6 mice were syngeneically, transplanted, grafts were perfused and stored in Perfadex with (treated) or without (control) a DPP IV enzymatic activity inhibitor (AB192). Transplantation was performed after 18h cold ischemia time; following 2-h reperfusion, grafts were analyzed for oxygenation, thiobarbituric acid-reactive substances, histomorphology, and immunohistochemistry was performed for leukocyte Ag 6, myeloperoxidase, hemoxygenase 1, vasoactive intestinal protein (VIP), and real-time PCR for VIP. Treatment with the DPP IV inhibitor AB192 resulted in significant improvement of gas exchange, less lipid oxidation, preservation of parenchymal ultrastructure, reduced neutrophil infiltration, reduced myeloperoxidase expression, increased hemoxygenase 1 expression, pronounced expression of VIP in alveolar macrophages and increased mRNA expression of VIP. Inhibition of intragraft DPP IV catalytic activity with AB192 strikingly ameliorates ischemia/reperfusion injury after extended ischemia. Furthermore, preservation of endogenous intragraft VIP levels correlate with maintaining lung function and structural integrity.

The effect of organ-specific CD26/DPP IV enzymatic activity inhibitor-preconditioning on acute pulmonary allograft rejection.

BACKGROUND: Systemic inhibition of serum CD26/dipeptidylpeptidase (DPP IV) enzymatic activity abrogated acute rejection of pulmonary allografts, whereas organ-specific inhibition ameliorated ischemia/reperfusion injury in syngeneic transplants. Here, we analyze the effect of allograft-specific inhibitor preconditioning on acute rejection in the presence of cyclosporine-based immunosuppressive therapy. METHODS: Orthotopic left single lung transplantation (Tx) in rats (LBNF1 to LEWIS). Control (n=5) grafts were flushed with Perfadex alone, whereas treated (n=5) transplants were perfused with Perfadex and AB192, a specific inhibitor of CD26/DPP IV enzymatic activity. All recipients were treated with 2.5 mg of cyclosporine A/kg per day subcutaneously after Tx. Recipients were sacrificed at day 5 after Tx, and oxygenation capacity was measured. In addition, staining for vasoactive intestinal peptide (VIP) and proliferating cell nuclear antigen (PCNA) at explantation (VIP) and at day 5 (VIP, PCNA) was performed with determination of protein levels for PCNA and mRNA for VIP. RESULTS: Grafts from treated versus controls showed significantly increased oxygenation capacity (P<.008), correlating with significantly less acute rejection (P<.02). PCNA staining and protein expression were significantly lower in perivascular and bronchial epithelial cells (P=.001) in treated versus controls. There was significantly higher staining for VIP at the time of Tx in alveolar macrophages in treated versus controls (P=.001), which was seen up to day 5 post-Tx in both macrophages and respiratory epithelium (P=.001) with elevated mRNA expression for VIP in treated animals. CONCLUSION: Perfusion with a specific inhibitor of CD26/DPP IV enzymatic activity was associated with sustained preservation of pulmonary VIP levels, correlating with an amelioration of the acute rejection cascade.

Immunosuppressive therapy in lung transplantation: state of the art.

The coming of age of lung transplantation is accompanied by an immunosuppressive armamentarium that has been brought forward from other transplant indications. Widely employed on the basis of few small randomized studies, and mostly single-center experience or empirical expert knowledge, anti-rejection therapeutic strategies in pulmonary transplantation have hardly been rigorously evaluated in large-scale prospective international trials. This review compiles the available findings on the use of current immunosuppressants in clinical lung transplantation, accentuating high level-of-evidence study results. Reporting on recent meeting and registry data, and assembling ongoing relevant trials from international databases, this article serves as an update on the state of the art of immunosuppression in lung transplantation.

Primary graft dysfunction in lung transplantation: the role of CD26/dipeptidylpeptidase IV and vasoactive intestinal peptide.

BACKGROUND: Enzymatic activity inhibition of CD26/dipeptidylpeptidase IV (CD26/DPP IV) attenuated short-term post-Tx (transplantation) ischemia-reperfusion injury after 18-hr-ischemia. Here, we investigated the effect of intragraft CD26/DPP IV catalytic inhibition on primary graft dysfunction during 7 day post-Tx, following extended ischemia. METHODS: A syngeneic rat (LEW [Lewis abstract]) orthotopic lung Tx model was used, grafts exposed to 18 hr cold ischemia before Tx. Controls were flushed and preserved in Perfadex, and harvested after 1 day (CON1) or 7 day (CON7) post-Tx. Investigational groups IN1, IN3, and IN7 grafts were perfused with and stored in Perfadex + inhibitor (AB192) and harvested at 1, 3, and 7 days post-Tx, respectively. Blood gas analysis, peak airway pressure (PAwP), wet/dry weight ratio, myeloperoxidase thiobarbituric acid reactive substances (TBARS), and staining for vasoactive intestinal peptide (VIP) were analyzed. RESULTS: IN1 versus CON1 showed preserved histology, increased pO2 (P<0.01), lowered PAwP (P<0.01), less edema (P<0.05) and decreased TBARS (P<0.05). Survival was better for IN7 versus CON7 (P<0.01). The course of AB192-perfused grafts from 1 to 7 days displayed improved values for pO2 (P<0.01), PAwP (P<0.01), edema (P<0.05), TBARS (P<0.05), and myeloperoxidase (P<0.05). Compared with controls, VIP was preserved during 18 hr ischemia in alveolar macrophages (P=0.0001) and respiratory epithelial cells (P=0.001). CONCLUSIONS: Perfusion with an inhibitor of CD26/DPP IV enzymatic activity significantly reduced the incidence and severity of pulmonary primary graft dysfunction and enabled recovery after extended ischemia. This is the first report that CD26/DPPIV inhibitor treatment increases local pulmonary VIP levels, which correlate with preserved ventilatory function and pulmonary structural integrity.

A mouse model of orthotopic, single-lung transplantation.

OBJECTIVES: Progress in studying acute and chronic pulmonary allograft rejection has been hampered by the lack of feasible experimental animal transplantation models. Contemporary approaches are limited by anatomic applicability (heterotopic tracheal implantation) and lack of genetic variability (rat model). To utilize the breadth of available genetic modifications in a physiologic setup, we optimized and validated a procedure of orthotopically transplanted, perfused, and ventilated single pulmonary transplantation in mice. METHODS: C57BL/6 mice served as recipient, with Balb/c as donor. At time of harvest, explanted lungs were perfused with Perfadex, and the heart-lung block excised. Under 30 to 40x magnification, vessels and bronchus were cuffed. Following left thoracotomy in the recipient, hilar structures were incised and cuff-anastomosed with the corresponding donor parts. Allogeneic and syngeneic transplantations (n = 12/group) were performed with a follow-up period of 5 days and up to 90 days, respectively. RESULTS: The success rate of lung transplantation in mice was 87.5% (21/24). Mean cold ischemia time was 32.3 +/- 3.7 minutes, and warm ischemia time was 30.8 +/- 9.5 minutes. Deaths were due to bleeding during dissection of the hilus and/or caused by thrombosis postoperatively. Allogeneic grafts were rejected by day 5; syngeneic grafts were slightly congested but mainly unchanged up to day 90 posttransplantation. CONCLUSIONS: Unilateral lung transplantation in mice can be performed in a standardized and controlled fashion with low mortality, comparable to the rat. Employing transgenic and knockout mice strains, this procedure holds great promise to advance the understanding of immunologic pathways in acute and chronic rejection in a physiologic model of pulmonary transplantation.

Airway complications after lung transplantation: risk factors, prevention and outcome.

PURPOSE: Anastomotic complications following lung transplantation (LuTx) have been described in up to 15% of patients. Challenging to treat, they are associated with high morbidity and a mortality rate of 2-5%. The aim of this study was to analyze the incidence of complications in a consecutive series of bronchial anastomosis after LuTx at our center and to delineate the potential risk factors. METHODS: Between 1992 and 2007, 441 bronchial anastomoses were performed in 235 patients. Indications for transplantation were cystic fibrosis (35.7%) emphysema (28.1%) pulmonary fibrosis (12.8%) and pulmonary hypertension (7.7%). There were 206 sequential bilateral and 28 single transplants including lobar engraftments in 20 cases. The donor bronchus was shortened to the plane of the lobar carina including the medial wall of the intermediate bronchus. Peribronchial tissue was left untouched. Anastomosis was carried out using a continuous absorbable running suture (PDS 4/0) at the membranous and interrupted sutures at the cartilaginous part. Six elective surveillance bronchoscopies were done monthly during the first half-year post-LuTx, with detailed assessment of the pre- and post-anastomotic airways. RESULTS: One-year survival since 2000 was 90.5%. In all 441 anastomoses performed, no significant dehiscence was observed. In one patient, a small fistula was detected and closed surgically on postoperative day five. Fungal membranes were found in 50% of the anastomoses at 1 month and in 14% at 6 months. Discrete narrowing of the anastomotic lumen without need for intervention was found in 4.9% of patients at 1 month and in 2.4% at 6 months. Age, cytomegalovirus status, induction therapy, immunosuppressive regimen, ischemic time, and ventilation time had no influence on bronchial healing. CONCLUSIONS: Clinically relevant bronchial anastomotic complications after LuTx can be avoided by use of a simple standardized surgical technique. Aggressive antibiotic and antifungal therapy might play an important supportive role.

Acute allograft rejection and immunosuppression: influence on endogenous melatonin secretion.

Melatonin displays a dose-dependent immunoregulatory effect in vitro and in vivo. Exogenous high-dose melatonin therapy exerted an immunosuppressive effect, abrogating acute rejection (AR), significantly prolonging transplant survival. Endogenous melatonin secretion, in response to heterotopic rat cardiac allograft transplantation (Tx), was investigated during the AR response and under standardized immunosuppressive maintenance therapy with cyclosporin A (CsA) and rapamycin (RPM). Recipients of syngeneic transplants, and recipients of allogeneic grafts, either untreated or receiving immunosuppressive therapy constituted the experimental groups. Endogenous circadian melatonin levels were measured at 07:00, 19:00, and 24:00 hr, using a novel radioimmunoassay (RIA) procedure, under standardized 12-hr-light/dark-conditions (light off: 19:00 hr; light on: 07:00 hr), before and after Tx. Neither the operative trauma, nor the challenge with a perfused allograft or the AR response influenced endogenous melatonin peak secretion. Immunosuppressive therapy with CsA led to a significant increase in peak secretion, measured for days 7 (212 +/- 40.7 pg/mL; P < 0.05), 14 (255 +/- 13.9 pg/mL; P < 0.001), and 21 (219 +/- 34 pg/mL; P < 0.01) after Tx, as compared with naïve animals (155 +/- 25.8 pg/mL). In contrast, treatment with RPM significantly decreased the melatonin peak post-Tx up to day 7 (87 +/- 25.2 pg/mL; P < 0.001), compared with naïve animals (155 +/- 25.8 pg/mL). These findings imply a robust nature of the endogenous circadian melatonin secretion kinetics, even against the background of profound allogeneic stimuli. Immunosuppressive maintenance therapy with CsA and RPM modulated early melatonin secretion, indicating a specific secondary action of these drugs. Further studies are necessary to disclose the long-term effect of immunosuppressive therapy on circadian melatonin secretion in transplant recipients.

Simplified rat lung transplantation by using a modified cuff technique.

Mizuta's cuff technique in rat lung transplantation (LT) model has some disadvantages, such as twisting of blood vessels or bronchus and being time-consuming, which complicate procedures for anastomosis. This study was performed to investigate the advantage of using a simplified cuff technique in LT. The anastomosis time was compared in two groups. In group I, Mizuta'scuff technique was performed in 50 rat orthotopic left lung transplants. In group II, a simple modified cuff technique was performed in 48 rat orthotopic left lung transplants. The successful rate of the new technique for anastomosis was 100%. No twist of vessels or bronchus and no bleeding or air leakage were observed in group II. The anastomosis time of group II was significantly less than for group I (11.2 +/- 2.1 min vs. 18.1 +/- 3.6 min, mean +/- SD, p < .01). This simple modified cuff technique led to less anastomosis time and avoided potential complications induced by the cuff-tail technique. It has been verified to be a safe, simple, and reproducible technique that can provide us with a more precise assessment in the rat LT model.

Intragraft DPP IV inhibition attenuates post-transplant pulmonary ischemia/reperfusion injury after extended ischemia.

BACKGROUND: CD26/DPP IV is a T-cell-membrane protein that cleaves dipeptides from extracellular peptides. Inhibition of its enzymatic activity using Pro-Pro-diphenylphosphonate derivatives has been shown to abrogate acute and accelerated rejection in models of cardiac and pulmonary allotransplantation. Here we investigated the effects of enzymatic DPP IV inhibition on ischemia/reperfusion (I/R) injury after extended ischemia before pulmonary transplantation. METHODS: A syngeneic rat orthotopic left-lung transplantation model was used. Group I donor lungs (controls) were flushed and preserved in Perfadex for 18 hours at 4 degrees C and then transplanted and reperfused for 2 hours. Group II grafts were perfused with and stored in Perfadex + 25 micromol/liter AB192 [bis(4-acetamidophenyl) 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate]. Group III lungs were perfused with Perfadex + AB192, and stored in Perfadex. After 2-hour reperfusion, oxygenation, peak airway pressure (PawP), graft wet/dry (W/D) weight ratio, myeloperoxidase activity, thiobarbituric acid-reactive substances, graft specific DPP IV enzymatic activities and histomorphology were analyzed. RESULTS: AB192 perfusion significantly reduced DPP IV intragraft enzymatic activity in Groups II and III. Compared with controls, transplants from Groups II and III showed significantly improved oxygenation capacity, PawP and W/D weight ratio, with lower intragraft lipid peroxidation; and preserved histologic structure. CONCLUSIONS: Targeting intragraft DPP IV enzymatic activity attenuated post-transplantation I/R injury and preserved early graft function after extended ischemia.

CD26/dipeptidylpeptidase IV-targeted therapy of acute lung rejection in rats.

BACKGROUND: CD26 is a T-cell co-stimulator, and interacts with adenosine deaminase, human immunodeficiency virus (HIV) Tat-1 protein and extracellular matrix. It possesses dipeptidylpeptidase IV (DPP IV) catalytic activity, which is linked to its co-stimulatory efficacy. We investigated the effect of specific DPP IV systemic activity inhibition on acute pulmonary rejection. METHODS: Rat single-lung transplantation (Tx) was performed (LBNF1/LEW donor/recipient) in two groups (n = 12). Group I (n = 6) received daily treatment with a Pro-Pro-diphenylphosphonate derivative (AB197), and Group II served as an untreated control. At Day 5 post-Tx, ventilatory parameters, cytotoxicity and mixed lymphocyte reaction were analyzed and staining for ISHLT rejection grade and proliferating cell nuclear antigen (PCNA) was performed. RESULTS: Treatment with AB192 abrogated acute rejection and preserved pulmonary function up to Day 5 post-Tx for PO2 (Group II: 24.9 +/- 6.9 mm Hg; Group I: 149.5 +/- 24.3 mm Hg; p < 0.001), PCO2 (Group II: 53.3 +/- 13.6 mm Hg; Group I: 39.0 +/- 9.8 mm Hg; p < 0.05) and peak airway pressure (Group II: 50.7 +/- 17.2 mm Hg; Group I: 20.2 +/- 10.0 mm Hg; p < 0.01). Controls showed moderate/severe rejection (ISHLT Grade A2 or 3), grafts from inhibited hosts revealed no/mild rejection (Grade A0 to 2: Group II: 2.8 +/- 0.3; Group I: 1.25 +/- 1.0; p < 0.005). Proliferating cell nuclear antigen (PCNA) staining of rejection-associated cellular infiltrates showed a significant reduction in positivity in perivascular infiltrates (34 +/- 11.5%; p < 0.05) and bronchial surface epithelium (31.7 +/- 10.6%; p < 0.05) in Group I vs Group II (55.9 +/- 8.4% and 57.2 +/- 4.5%). CONCLUSIONS: Irreversible enzymatic inhibition of DPP IV has been shown to abrogate acute pulmonary rejection, maintain pulmonary function, and preserve histomorphologic architecture. These results extend earlier findings and illustrate the role of CD26/DPP IV in alloantigen-mediated immune responses.

Lung-volume reduction surgery as an alternative or bridging procedure to lung transplantation.

BACKGROUND: In this study, we prospectively analyzed the functional outcome and the survival after lung-volume reduction surgery (LVRS) in patients with end-stage emphysema who were initially potential candidates for lung transplantation (LTX), and investigated the impact of LVRS on posttransplant course in patients who underwent LTX after LVRS. METHODS: Of the 216 patients who underwent LVRS between 1994 and 2005, 58 were potential candidates for LTX at the time of LVRS (age 65 years or younger, forced expiratory volume in 1 second 25% of predicted or less; LVRS/LTX group). Lung-volume reduction surgery was performed by means of video-assisted, bilateral stapled resection of target areas. During the same period, 31 patients underwent primary LTX for end-stage emphysema (LTX group). Spirometry, plethysmography, carbon monoxide diffusing capacity, 6-minute walking distance, and dyspnea score were assessed preoperatively and at predetermined times after operation. Survival analysis was performed by use of the Kaplan-Meier method. RESULTS: All the functional variables significantly improved after LVRS and peaked within the first year. Subjective improvement was observed for up to 5 years after LVRS, and 53% (31 of 58) of the patients were still alive and had not undergone transplantation after a median follow-up of 44 months. Fourteen percent (8 of 58) of the patients underwent secondary LTX because of progressive worsening of the respiratory function after a median bridging time between LVRS and LTX of 33 months. Postoperative recovery after transplantation and median survival time were comparable between the 8 patients of the LVRS/LTX group and the 31 patients of the LTX group (96.5 months versus 118.5 months, p = 0.9). CONCLUSIONS: Lung-volume reduction surgery can significantly improve symptoms and lung function in selected patients who are initially potential candidates for LTX. Lung-volume reduction surgery can allow the postponement of LTX for up to 4 to 5 years and does not impair the chances for a subsequent successful LTX.