Tissue factor regulates autophagy in pulmonary artery endothelial cells from chronic thromboembolic pulmonary hypertension rats via the p38 MAPK-FoxO1 pathway.

AIMS: To detect the expression of autophagy components, p38 MAPK (p38) and phosphorylated forkhead box transcription factor O-1 (pFoxO1) in pulmonary vascular endothelial cells of chronic thromboembolic pulmonary hypertension (CTEPH) rats and to investigate the possible mechanism through which tissue factor (TF) regulates autophagy. METHODS: Pulmonary artery endothelial cells (PAECs) were isolated from CTEPH (CTEPH group) and healthy rats (control group (ctrl group)) which were cocultured with TF at different time points including 12 h, 24 h, 48 h and doses including 0 nM,10 nM, 100 nM, 1µM, 10µM, 100µM and cocultured with TFPI at 48 h including 0 nM, 2.5 nM, 5 nM. The expression of forkhead box transcription factor O-1 (FoxO1), pFoxO1, p38, Beclin-1 and LC3B in PAECs was measured. Coimmunoprecipitation (co-IP) assays were used to detect the interaction between FoxO1 and LC3. RESULTS: The protein expression of p-FoxO1/FoxO1 was significantly lower in the CTEPH groups (cocultured with TF from 0 nM to 100 µM) than in the ctrl group at 12 h, 24 h, and 48 h (P < 0.05) and was significantly lower in the CTEPH groups (cocultured with TFPI from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of p38 in the CTEPH groups treated with 0 nM, 10 nM, 100 nM or 1 µM TF for 48 h significantly increased than ctrl groups (P < 0.05) and was significantly increased in the CTEPH groups (cocultured with TFPI concentration from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of Beclin1 at the same concentration (cocultured with TF from 0 nM to 100 µM) was significantly lower in the CTEPH groups than ctrl groups after 24 h and 48 h (P < 0.05) and was significantly decreased in the CTEPH groups (cocultured with TFPI concentration from 2.5 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of LC3-II/LC3-I at the same concentration (cocultured with TF 0 nM, 1 µM, 10 µM, and 100 µM) was significantly lower in the CTEPH than in the ctrl groups after 12 h (P < 0.05) and was significantly lower in the CTEPH groups (cocultured with TFPI concentration from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). There were close interactions between FoxO1 and LC3 in the control and CTEPH groups at different doses and time points. CONCLUSION: The autophagic activity of PAECs from CTEPH rats was disrupted. TF, FoxO1 and p38 MAPK play key roles in the autophagic activity of PAECs. TF may regulate autophagic activity through the p38 MAPK-FoxO1 pathway.

The value of intratumoral and peritumoral radiomics features in differentiating early-stage lung invasive adenocarcinoma (≤3 cm) subtypes.

Background: The identification of different subtypes of early-stage lung invasive adenocarcinoma before surgery contributes to the precision treatment. Radiomics could be one of the effective and noninvasive identification methods. The value of peritumoral radiomics in predicting the subtypes of early-stage lung invasive adenocarcinoma perhaps clinically useful. Methods: This retrospective study included 937 lung adenocarcinomas which were randomly divided into the training set (n=655) and testing set (n=282) with a ratio of 7:3. This study used the univariate and multivariate analysis to choose independent clinical predictors. Radiomics features were extracted from 18 regions of interest (1 intratumoral region and 17 peritumoral regions). Independent and conjoint prediction models were constructed based on radiomics and clinical features. The performance of the models was evaluated using receiver operating characteristic (ROC) curves, accuracy (ACC), sensitivity (SEN), and specificity (SPE). Significant differences between areas under the ROC (AUCs) were estimated using in the Delong test. Results: Patient age, smoking history, carcinoembryonic antigen (CEA), lesion location, length, width and clinic behavior were the independent predictors of differentiating early-stage lung invasive adenocarcinoma (≤3 cm) subtypes. The highest AUC value among the 19 independent models was obtained for the PTV0~+3 radiomics model with 0.849 for the training set and 0.854 for the testing set. As the peritumoral distance increased, the predictive power of the models decreased. The radiomics-clinical conjoint model was statistically significantly different from the other models in the Delong test (P<0.05). Conclusions: The intratumoral and peritumoral regions contained a wealth of clinical information. The diagnostic efficacy of intra-peritumoral radiomics combined clinical model was further improved, which was particularly important for preoperative staging and treatment decision-making.

Prediction of CD3 T cells and CD8 T cells expression levels in non-small cell lung cancer based on radiomic features of CT images.

Background: In this work, radiomics characteristics based on CT scans were used to build a model for preoperative evaluation of CD3 and CD8 T cells expression levels in patients with non-small cell lung cancer (NSCLC). Methods: Two radiomics models for evaluating tumor-infiltrating CD3 and CD8 T cells were created and validated using computed tomography (CT) images and pathology information from NSCLC patients. From January 2020 to December 2021, 105 NSCLC patients with surgical and histological confirmation underwent this retrospective analysis. Immunohistochemistry (IHC) was used to determine CD3 and CD8 T cells expression, and all patients were classified into groups with high and low CD3 T cells expression and high and low CD8 T cells expression. The CT area of interest had 1316 radiomic characteristics that were retrieved. The minimal absolute shrinkage and selection operator (Lasso) technique was used to choose components from the IHC data, and two radiomics models based on CD3 and CD8 T cells abundance were created. Receiver operating characteristic (ROC), calibration curve, and decision curve analyses were used to examine the models' ability to discriminate and their clinical relevance (DCA). Results: A CD3 T cells radiomics model with 10 radiological characteristics and a CD8 T cells radiomics model with 6 radiological features that we created both demonstrated strong discrimination in the training and validation cohorts. The CD3 radiomics model has an area under the curve (AUC) of 0.943 (95% CI 0.886-1), sensitivities, specificities, and accuracy of 96%, 89%, and 93%, respectively, in the validation cohort. The AUC of the CD8 radiomics model was 0.837 (95% CI 0.745-0.930) in the validation cohort, with sensitivity, specificity, and accuracy values of 70%, 93%, and 80%, respectively. Patients with high levels of CD3 and CD8 expression had better radiographic results than patients with low levels of expression in both cohorts (p<0.05). Both radiomic models were therapeutically useful, as demonstrated by DCA. Conclusions: When making judgments on therapeutic immunotherapy, CT-based radiomic models can be utilized as a non-invasive way to evaluate the expression of tumor-infiltrating CD3 and CD8 T cells in NSCLC patients.

Feasibility of customizing titanium implant with three-dimensional CT imaging of low dose in skull.

OBJECT: To explore the feasibility and practicability of making virtual three-dimensional model of skull defect and customizing titanium implant by skull three-dimensional CT examination of low dose. METHODS: Sixty patients with skull defects who underwent skull three-dimensional CT before cranioplasty were randomly divided into 4 groups: group A (conventional dose 120 peak Kilovoltage (kVp), 150 tube current time product (mAs)), low dose group B (120 kVp, 50 mAs), low dose group C (100 kVp, 50 mAs), low dose group D (100 kVp, 30 mAs). After the scanning, we compared radiation doses and image quality among the groups. The CT data were sent to the reconstruction company to produce accurate titanium implants, and neurosurgeons performed cranioplasty. After the operation, patients immediately underwent head CT scans to confirm the accuracy of the implantation position, and a series of clinical functions were evaluated. RESULTS: There were significant differences in dose length product (DLP) and effective dose (ED) among the 4 groups (P < .001). The volume CT dose index (CDTIvol), DLP, and ED in group D were, respectively, 87.1%, 86.9%, and 87.3% lower than those in group A (P < .001). All images quality were at or above the general level, and there was no statistical difference (P > .05). Titanium implants were successfully manufactured, every cranioplasty was carried out smoothly, and the clinical function of patients recovered well. CONCLUSION: Customizing titanium implant with three-dimensional CT imaging of low dose in skull not only met the clinical requirements, but also significantly reduced the radiation dose and hazard.

Study on the dynamic change law and correlation between CT imaging manifestations and cellular immunity of 2019 novel coronavirus disease.

PURPOSE: To explore the dynamic changes and correlation between CT imaging manifestations and cellular immunity of COVID-19. MATERIALS AND METHODS: This retrospective review analyzed 23 patients with COVID-19, including 13 males and 10 females aged 27-70 years, with an average age of 48 years. Patients were divided into two groups: group A with 11 critical-severe patients, and group B with 12 common-mild patients. Clinical, laboratory, and radiological data were collected and analyzed. RESULTS: LYM, LYM (%), CD3+, CD4+, and CD8+ decreased, while NEU (%), CRP, and CT scores increased in all patients, WBC in group A increased. In group A, on day 10-12 after disease onset, CT scores and CRP reached the highest point, and day 13-15 LYM, LYM (%) reached the lowest but NEU (%) and WBC reached the highest, CD3+, CD4+ and CD8+ were at the lowest on day 10-15. In group B, on day 7-9, CT scores, NEU (%) and CRP reached the peak, but LYM, LYM (%), CD3+, CD4+ and CD8+ reached the lowest. In all patients, CT scores had a significantly negative correlation with CD3+, CD4+, CD8+, LYM (%), and LYM (p = 0.001, r = - 0.797; p = 0.008, r = - 0.698; p = 0.002, r = - 0.775; p < 0.001, r = - 0.785; p = 0.021, r = - 0.571, respectively), and a significantly positive correlation with WBC and NEU (%) (p < 0.001, r = 0.785; p = 0.003, r = 0.691, respectively). CONCLUSION: Dynamic changes of CT manifestations and cellular immunity of patients with COVID-19 were regular and correlation was high between these two parameters.

The role of inflammation in a rat model of chronic thromboembolic pulmonary hypertension induced by carrageenan.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition arising from the thrombus and obstructive remodeling of the pulmonary arteries, which causes a significant morbidity and mortality. Although the modern treatment in CTEPH has been significant advanced both in surgical and medical treatment, none can claim to cure the disease, largely because of our limited understanding of the underlying pathogenesis of the disease and lack of a reliable CTEPH animal model to study for. Recently, inflammation has been accepted as a common pathway through which various risk factors trigger venous thrombo-embolism (VTE) formation, we describe a novel mouse model of CTEPH which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of CTEPH in humans, to open a new horizons of inflammation in CTEPH. METHODS: By administering a pulmonary embolism (PE) protocol (comprising 3 sequential left jugular vein injections of autologous blood clots) to 8-week-old male Sprague Dawley (SD) rats using tranexamic acid (200 mg/kg.d) to inhibit fibrinolysis and injecting additional carrageenan (20 mg/kg, once a week) to create perivascular inflammation, we successfully generated a CTEPH animal model. By monitoring the mean pulmonary artery pressure (mPAP) and the histopathological change to evaluate the CTEPH model. By detecting the RT-PCR, western blot, TUNEL, and immunohistochemistry in the sub-groups to find the potential mechanism of inflammation may work in the pulmonary vascular remolding. RESULTS: In this study, rats with CTEPH exhibited pronounced pulmonary vascular remolding with higher vessel wall area/total area (WA/TA) ratio in comparison to the control rats (85.41%±7.37% vs. 76.41%±5.97%, P<0.05), the mPAP (25.51±1.13 vs. 15.92±1.13 mmHg, P<0.05). Significant differences in mean pulmonary artery pressure (mPAP) values were observed between rats injected solely with clots and those injected with both clots and carrageenan (25.51±1.13 vs. 29.82±1.26 mmHg, P<0.05, respectively). Furthermore, following the third embolization, thrombi and intimal hyperplasia occurred in the pulmonary artery. In addition, repeated embolization elevated mRNA and protein levels of tumor necrosis factor-α (TNF-α), NF-κB/p65, and B-cell lymphoma-2 (BCL-2), but decreased BAX expression in a time-dependent manner. CONCLUSIONS: Take advantage of the inflammation to trigger VTE formation, we successfully generated a CTEPH animal model. Inflammation may play a crucial role in the pathogenesis and progression of CTEPH by inhibiting endothelial cell apoptosis. Understanding the role of inflammation in CTEPH may not only help to determine the optimal treatment options but also may aid in the development of future preventative strategies, since current anticoagulation treatment regimens are not designed to inhibit inflammation.

Analysis of PROC and PROS1 single nucleotide polymorphisms in a thrombophilia family.

OBJECTIVE: The aim of this study was to assess the association of single nucleotide polymorphisms (SNPs) in protein C (PROC) and protein S (PROS1) genes with deep venous thrombosis (DVT) in a thrombophilia family. METHODS: DNA were extracted from blood of participants. Five PROC SNPs and 11 PROS1 SNPs were selected from the Hapmap and 1000 Genomes databases. The minor allele frequencies (MAFs) of SNPs in the thrombophilia family (Group I) and healthy controls (Group II) were detected. SNPs were analysed by Chi-square, logistic regression and linkage disequilibrium patterns. RESULTS: MAFs for all 16 SNPs were greater than 0.05. Chi-square analysis showed significant differences between Group I and Group II in the frequency of mutant alleles of rs1799808, rs5936, rs6123, rs12634349, rs6441600 and rs13062355 SNPs (P < .05). Logistic regression analysis found that mutant alleles of rs1799808, rs6441600 and rs13062355 SNPs may contribute to DVT in this family (OR > 1, L95 > 1). Linkage disequilibrium was found among 15 of the PROC and PROS SNPs. CONCLUSIONS: Single nucleotide polymorphisms (SNPs) of PROC and PROS1 may be closely associated with DVT in this thrombophilia family. Mutant alleles of rs1799808, rs6441600 and rs13062355 SNPs may contribute to DVT, whereas mutant alleles of rs1799810, rs6123 and rs12634349 may protect individuals from DVT. With the exception of rs9681204, there was linkage disequilibrium between PROC and PROS1 SNPs. We found that 12 haplotypes were in linkage disequilibrium, but linkage disequilibrium was strong in only eight of these (frequency >5%).

Role of monocyte tissue factor on patients with non-small cell lung cancer.

BACKGROUND: To examine the expression of D-dimer, fibrinogen (FIB), leukocyte, C-reactive protein (CRP) and tissue factor (TF) released from monocyte in non-small cell lung cancer (NSCLC) patients with or without venous thromboembolism (VTE) and analyse the correlation, to explore the possible mechanisms. METHODS: Seventy-two patients confirmed the diagnosis of lung cancer, among whom 10 with VTE were enrolled into the study from November 2012 to January 2014 in the First Affiliated Hospital of Fujian Medical University and 30 healthy subjects were also enrolled as the control group. Ficoll and Percoll density gradient centrifugation separated of peripheral blood monocyte. Monocyte TF mRNA expression was detected using reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: There were significant differences in different stages of the cancer (P < .05) and no significance among the histopathologic types (P > .05) for the expression of monocyte TF mRNA in NSCLC patients, its expression was significantly higher in cancer with lymph node metastasis than those without lymph node metastasis (P < .01). Meanwhile, in NSCLC patients with VTE, the expression of monocyte TF mRNA was significantly higher than that in patients without VTE (P < .01). Difference of the survival curves between the low monocyte TF mRNA expression and the high monocyte TF mRNA expression was significant (Log-rank x2 = 4.923, P < .05). CONCLUSIONS: Monocyte TF may be a relevant source of TF-mediated thrombogenicity in NSCLC patients and may be associated with prognosis in NSCLC.

Imaging findings of gastric plexiform fibromyxoma with a cystic change: A case report and review of literature.

RATIONALE: Plexiform fibromyxoma (PF) is an extremely rare mesenchymal tumor of the stomach, and its radiological findings have not been well described. Here, we analyzed the imaging features of a case of PF. To our knowledge, this is a rare reported case with a remarkable cystic change in the imaging literature. PATIENT CONCERNS: A previously healthy 50-year-old woman presented with a 1-day history of abdominal pain. Then, she underwent computed tomography (CT) and magnetic resonance imaging (MRI). A cystic-solid well-circumscribed extraluminal mass was located in the posterior wall of the gastric upper body. The solid portion appeared as heterogeneous attenuation/intensity with progressive enhancement while the cystic region had no enhancement. DIAGNOSES: The potential for malignancy could not be excluded. INTERVENTIONS: Laparoscopic partial gastric resection was performed. OUTCOMES: Based on pathological findings, a diagnosis of PF was made. The patient was alive without any recurrence or metastasis of the tumor after 2 years of follow-up. LESSONS: As far as we know, a gastric PF with a remarkable cystic change has never been reported. Additionally, the tumor exhibited a progressive enhancement pattern which is a characteristic radiographic feature in our case. Our report may help increase the awareness of this rare but important new disease entity.

An irregular pulmonary nodule was confirmed diagnosis of aspiration pneumonia by finding plant cells through rapid on-site evaluation.

BACKGROUND: Rapid on-site evaluation (ROSE) is a method which is often used in quick-staining cytology in the tumour diagnostic field, and results in a significant decrease in diagnostic time and cost. However, we have not found any previous report on the ROSE method for diagnosing aspiration pneumonia. METHODS: We would like to discuss the case of a patient with an irregular pulmonary nodule in the left lower lobar bronchus who had a confirmed diagnosis of aspiration pneumonia through ROSE stained by Diff-Quik methods during bronchoscopy. RESULTS: Through ROSE, which we were able to perform within just 1 min, we observed the plant cells on the smear under the microscope. The Giemsa stain of the specimen, which would take much more time than Diff-Quik, also revealed the plant cells. CONCLUSION: ROSE for the specimen from the bronchoscopy could be done for the patient who has developed an unexplained pulmonary nodule and is helpful. If the non-human cells such as plant cells are found from the ROSE, aspiration pneumonia can be diagnosed immediately and the corresponding therapy may be performed, which may significantly shorten hospital stay, reduce hospital costs and improve patient outcomes.

Expression of tissue factor and forkhead box transcription factor O-1 in a rat model for chronic thromboembolic pulmonary hypertension.

Few reports have examined tissue factor (TF) and forkhead box transcription factor O-1 (FoxO1) expression in chronic thromboembolic pulmonary hypertension (CTEPH) animal models. To investigate the role of TF and FoxO1 and their interactions during CTEPH pathogenesis in a rat model. Autologous blood clots were repeatedly injected into the pulmonary arteries through right jugular vein to induce a rat model of CTEPH. Hemodynamic parameters, histopathology, and TF and FoxO1expression levels were detected. The mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance and vessel wall area/total area (WA/TA) ratio in the experiment group increased significantly than sham group (P < 0.05). The cardiac output in the 1-, 2-, and 4-week groups decreased significantly (P < 0.05) when compared to sham group. TF mRNA expression levels in the experiment group increased significantly than sham group (P < 0.05). FoxO1 mRNA and protein expression levels were lower in the experiment group than sham group (P < 0.05). The mPAP had a positive correlation with WA/TA ratio (r = 0.45, P = 0.01). TF mRNA expression had a positive correlation with WA/TA ratio (r = 0.374, P = 0.035) and a positive correlation with mPAP (r = 0.48, P= 0.005). FoxO1 mRNA expression had a negative correlation trend with the WA/TA ratio (r = -0.297, P = 0.099) and a negative correlation trend with mPAP (r = -0.34, P = 0.057). TF mRNA expression had a negative correlation with FoxO1 mRNA expression (r = -0.62, P < 0.001). A rat model of CTEPH can be successfully established by the injection of autologous blood clots into the pulmonary artery. TF and FoxO1 may play a key role in vascular remodeling during CTEPH pathogenesis.

The role of tissue factor and autophagy in pulmonary vascular remodeling in a rat model for chronic thromboembolic pulmonary hypertension.

BACKGROUND: Few reports have examined tissue factor (TF) and autophagy expression in chronic pulmonary thromboembolic hypertension (CTEPH) animal models. OBJECTIVES: To investigate the role of tissue factor (TF), autophagy and their interactions during chronic thromboembolic pulmonary hypertension (CTEPH) pathogenesis in a rat model. METHODS: Autologous blood clots were repeatedly injected into the left jugular vein of rats with injecting endogenous fibrinolysis inhibitor tranexamic acid (TXA). Mean pulmonary arterial pressure (mPAP), histopathology and TF, Beclin-1 and microtubule-associated protein 1 light chain (LC3) expression levels were detected. RESULTS: The mPAP and vessel wall area/total area (WA/TA) ratio in the experiment group increased significantly (P < 0.05). TF mRNA and protein expression levels in the experiment group increased significantly (P < 0.05). Beclin-1 and LC3B mRNA and protein expression levels were lower in the experiment group (P < 0.05). The mPAP had a positive correlation with WA/TA ratio (r = 0.955, P < 0.05). Beclin-1 and LC3B protein expression had a negative correlation with the WA/TA ratio (r = -0.963, P < 0.05, r = -0.965, P < 0.05, respectively). TF protein expression had a negative correlation with both Beclin-1 and LC3B protein expression (r = -0.995, P <0.05, r = -0972, P < 0.05, respectively). CONCLUSIONS: A rat model of CTEPH can be established by repeatedly introducing autologous blood clots into the pulmonary artery with injecting TXA. TF and autophagy may play a key role during CTEPH pathogenesis, especially in vascular remodeling.

Close concordance between pulmonary angiography and pathology in a canine model with chronic pulmonary thromboembolism and pathological mechanisms after lung ischemia reperfusion injury.

To investigate the pulmonary angiography and pathology in a canine model with chronic pulmonary thromboembolism (PTE). The cylindrical blood clots were selectively introduced into the left (n = 10) or right (n = 20) lower pulmonary arteries of dogs. Pulmonary arteriography (PA) was performed before or after embolization. The values after embolization and baseline of mean pulmonary arterial pressure, pulmonary vascular resistance, cardiac output had changed. After 1 or 2 weeks' embolization, local PA demonstrated the abrupt cut-off perfusion defects or webs, bands, and abrupt vascular narrowing. 2 weeks after embolization, the pathology showed that the fibrin networks of the thrombi had multiple recanalization channels, and pulmonary artery had the concentric, lamellar (onion-like) intimal hyperplasia, multilayered, irregular arrangements of endothelial cells, and the infiltration of inflammatory cells. After embolectomy-mediated reperfusion, 2 weeks' subgroup showed destroyed and incomplete alveolar structures, and a large number of exudative cells, primarily neutrophils, and exudate. There close concordance between pulmonary angiography and pathology in a canine model with chronic PTE. The LIRI mechanisms after embolectomy-mediated reperfusion involve the destroyed, incomplete alveolar structures, and infiltration of inflammatory cells, primarily neutrophils.

The role of mononuclear cell tissue factor and inflammatory cytokines in patients with chronic thromboembolic pulmonary hypertension.

Thrombosis and inflammation are two major factors underlying chronic thromboembolic pulmonary hypertension (CTEPH). Tissue factor (TF), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) may play critical roles in the process of CTEPH thrombosis and pulmonary vascular remodeling. Ten patients with a confirmed diagnosis of CTEPH, 20 patients with acute pulmonary thromboembolism and 15 patients with other types of pulmonary hypertension were enrolled in this study, along with 20 healthy subjects as the control group. The immunoturbidimetric method was used to determine the plasma content of CRP. The plasma levels of TNF-α, MCP-1, and TF antigen were measured by an enzyme-linked immunosorbent assay, and TF activity was measured by the chromogenic substrate method. Percoll density gradient centrifugation was used to separate peripheral blood mononuclear cells from plasma. The level of monocyte TF mRNA was examined by reverse transcriptase-polymerase chain reaction. The correlations between all indices described above were analyzed. In CTEPH patients, the expression of CRP, TNF-α, and MCP-1 was significantly higher than that in controls (P < 0.05). The levels of TF activity, TF antigen, and TF mRNA in monocyte cells were increased in CTEPH patients when compared with control subjects, but only the TF antigen and TF mRNA levels were significantly different (P < 0.05). In CTEPH patients, levels of CRP, MCP-1, and TNF-α significantly correlated with the level of TF antigen in plasma. TF gene expression was increased in patients with CTEPH, suggesting that blood-borne TF mainly comes from mononuclear cells. TF expression significantly correlated with levels of CRP, TNF-α and MCP-1. These factors may play an important role in the development of CTEPH via the inflammation-coagulation-thrombosis cycle.

Inflammatory response and pneumocyte apoptosis during lung ischemia-reperfusion injury in an experimental pulmonary thromboembolism model.

Lung ischemia-reperfusion injury (LIRI) may occur in the region of the affected lung after reperfusion therapy. The inflammatory response mechanisms related to LIRI in pulmonary thromboembolism (PTE), especially in chronic PTE, need to be studied further. In a PTE model, inflammatory response and apoptosis may occur during LIRI and nitric oxide (NO) inhalation may alleviate the inflammatory response and apoptosis of pneumocytes during LIRI. A PTE canine model was established through blood clot embolism to the right lower lobar pulmonary artery. Two weeks later, we performed embolectomy with reperfusion to examine the LIRI changes among different groups. In particular, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2), serum concentrations of tumor necrosis factor-α (TNF-α), myeloperoxidase concentrations in lung homogenates, alveolar polymorphonuclear neutrophils (PMNs), lobar lung wet to dry ratio (W/D ratio), apoptotic pneumocytes, and lung sample ultrastructure were assessed. The PaO2/FiO2 in the NO inhalation group increased significantly when compared with the reperfusion group 4 and 6 h after reperfusion (368.83 ± 55.29 vs. 287.90 ± 54.84 mmHg, P < 0.05 and 380.63 ± 56.83 vs. 292.83 ± 6 0.34 mmHg, P < 0.05, respectively). In the NO inhalation group, TNF-α concentrations and alveolar PMN infiltration were significantly decreased as compared with those of the reperfusion group, 6 h after reperfusion (7.28 ± 1.49 vs. 8.90 ± 1.43 pg/mL, P < 0.05 and [(19 ± 6)/10 high power field (HPF) vs. (31 ± 11)/10 HPF, P < 0.05, respectively]. The amount of apoptotic pneumocytes in the lower lobar lung was negatively correlated with the arterial blood PaO2/FiO2, presented a positive correlation trend with the W/D ratio of the lower lobar lung, and a positive correlation with alveolar PMN in the reperfusion group and NO inhalation group. NO provided at 20 ppm for 6 h significantly alleviated LIRI in the PTE model. Our data indicate that, during LIRI, an obvious inflammatory response and apoptosis occur in our PTE model and NO inhalation may be useful in treating LIRI by alleviating the inflammatory response and pneumocyte apoptosis. This potential application warrants further investigation.

Beneficial effects of inhaled NO on apoptotic pneumocytes in pulmonary thromboembolism model.

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) may occur in the region of the affected lung after reperfusion therapy. Inhaled NO may be useful in treating acute and chronic pulmonary thromboembolism (PTE) due to the biological effect property of NO. METHODS: A PTE canine model was established through selectively embolizing blood clots to an intended right lower lobar pulmonary artery. PaO2/FiO2, the mPAP and PVR were investigated at the time points of 2, 4, 6 hours after inhaled NO. Masson's trichrome stain, apoptotic pneumocytes and lung sample ultrastructure were also investigated among different groups. RESULTS: The PaO2/FiO2 in the Inhaled NO group increased significantly when compared with the Reperfusion group at time points of 4 and 6 hours after reperfusion, mPAP decreased significantly at point of 2 hours and the PVR decreased significantly at point of 6 hours after reperfusion. The amounts of apoptotic type II pneumocytes in the lower lobar lung have negative correlation trend with the arterial blood PaO2/FiO2 in Reperfusion group and Inhaled NO group. Inhaled nitric oxide given at 20 ppm for 6 hours can significantly alleviate the LIRI in the model. CONCLUSIONS: Dramatic physiological improvements are seen during the therapeutic use of inhaled NO in pulmonary thromboembolism canine model. Inhaled NO may be useful in treating LIRI in acute or chronic PTE by alleviating apoptotic type II pneumocytes. This potential application warrants further investigation.