BACKGROUND AND OBJECTIVES: Macitentan (MAC) reduces morbidity and mortality among advanced-stage pulmonary arterial hypertension (PAH) patients. However, data regarding the histopathologic and hemodynamic benefits of MAC treatment at an early stage of PAH is lacking. METHODS: One week after monocrotaline (MCT) injection, rats were randomly assigned to MAC (n=16), MAC combined with sildenafil (SIL) (MAC+SIL, n=16), or normal saline (MCT, n=16). Twelve sham rats (Sham) were included for comparison. Right ventricular (RV) systolic function was assessed via echocardiography as the RV fractional area change (RV-FAC). An invasive pressure-volume analysis using a Millar conductance catheter was performed 7 weeks after MCT injection. Rats were subsequently euthanized for histopathologic analysis. RESULTS: RV-right atrial pressure gradient on echocardiography was significantly increased 3 weeks after MCT injection, but was maintained in the Sham. RV-FAC was less deteriorated in the MAC, compared to that in the MCT (44±3% vs. 25±7%, p < 0.05), and the co-administration of SIL showed no additional benefit (45±8%, p > 0.05 vs. the MAC). On invasive hemodynamic analyses, RV end-systolic (196±78 µL) and end-diastolic volumes (310±86 µL), pulmonary artery systolic pressure (89±7.2 mmHg), and end-systolic pressure-volume relationship (−254±25.1) were significantly worse in the MCT vs. in the MAC (101±45 µL, 235±55 µL, 40±10.5 mmHg, and −145±42.1, respectively) and MAC+SIL (109±47 µL, 242±46 µL, 38±9.2 mmHg, and −151±39.2, respectively) (all p < 0.05). However, the MAC and MAC+SIL did not differ (all p > 0.05). On histopathology, both RV and lung fibrosis were significantly reduced in the MAC and MAC+SIL vs. in the MCT (all p < 0.05); the 2 treatment groups did not differ. CONCLUSIONS: MAC treatment at an earlier stage significantly attenuated experimental PAH progression hemodynamically and histopathologically.
Animals ; Atrial Pressure ; Blood Pressure ; Catheters ; Echocardiography ; Fibrosis ; Hemodynamics ; Humans ; Hypertension ; Hypertension, Pulmonary ; Lung ; Models, Animal ; Monocrotaline ; Mortality ; Pathology ; Pulmonary Artery ; Rats ; Sildenafil Citrate

OBJECTIVESevere Epstein-Barr (EB) virus infection is potentially a devastating process that often leads to death encountered in pediatrics recently. Inappropriate control of EB virus replication may cause severe infection resulting in multiple organ dysfunction. However, little information is available on pulmonary complications associated with EB virus infection. The aim of the present study was to investigate severe EB virus (EBV) infection complicated with lung injury in pediatric intensive care unit (PICU), including clinical characteristics, laboratory or imaging feature and outcomes.

METHODA total of 45 children with severe EBV infection seen in PICU of Shanghai Children's Hospital between January 2011 and December 2014 were retrospectively reviewed. According to clinical characteristics and imaging feature, 45 children were divided into non-lung injury group (n =27), lung injury without pulmonary fibrosis group(n = 12) and pulmonary fibrosis group (n = 6).

RESULTIn totally 45 cases of severe EBV infection, 21 (46.7%) were male and 24 (53. 3%) were female, mean age was 2. 4 years; 18 cases were complicated with lung injury, including 8 male and 10 female, median age was 31. 2 months. All of 18 cases presented with fever and cough, 15 of them exhibited dyspnea,12 cases were complicated with gasping, and 6 cases with ARDS. Eight cases accepted mechanical ventilation for acute respiratory distress; 6 cases who developed pulmonary fibrosis had tachypnea, refractory hypoxemia and hypercapnia, severe pulmonary air leak. The average EBV-DNA level in peripheral blood was 4. 42 x 10(6) copies/ml (range: 3. 25 x 10(3) - 6.59 x 10(7) copies/ml). Anti-EBV antibodies were positive in 41 cases, 18 cases were positive (+) for VCA-IgM, 15 cases were VCA-IgG and EA-IgG (+), 8 cases VCA-IgM and VCA-IgG (+). The radiographic findings revealed pulmonary interstitial infiltrates in all 18 cases with lung injury, 4 cases with segmental consolidation and 2 cases showed pleural effusions. HRCT scanning found EBV associated fibrosis including multifocal patches and diffuse ground-glass attenuation in both lungs, reticular opacities and honeycombing changes were observed 4 weeks after illness onset. There were significant differences in respiratory failure, PICU stay (days), Pediatric risk of mortality III (PRISM III) and pediatric clinical illness score(PCIS), serum TNF-α, EBV-DNA levels, percentage of NK cells and CD4+/CD8+ T cell ratio among non-lung injury group, lung injury without pulmonary fibrosis group and pulmonary fibrosis group (X2 =27. 12, F = 85. 23, 78. 23, 88. 68, 323. 80, 7. 35, χ2 = 6. 71, 12. 15; all P < 0. 05). COX regression analysis revealed that EBV-DNA and serum TNF-α levels were correlated with pulmonary fibrosis significantly (OR = 3. 92, P = 0. 04; OR = 5. 95, P = 0. 01). The patients with EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) had higher incidence of pulmonary fibrosis compared with non-EB-HLH (70% vs. 13%, χ2 = 4. 82, P = 0. 03). Of 18 cases, 8 cases died, including 3 cases with pulmonary fibrosis. The surviving cases with pulmonary fibrosis needed longer additional oxygen. Chest HRCT imaging of 3 cases with pulmonary fibrosis was improved at 6 months and oxygen therapy was discontinued at 18 months after discharge.

CONCLUSIONEB virus infection complicated with lung injury had higher incidence of respiratory failure, pulmonary fibrosis with a fatal outcome. EBV-DNA and serum TNF-α level were found to be statistically significant indicators of pulmonary fibrosis. Pulmonary fibrosis associated with severe EB virus infection may be reversible.

Antibodies, Viral ; blood ; CD4-CD8 Ratio ; Child, Preschool ; China ; DNA, Viral ; blood ; Epstein-Barr Virus Infections ; pathology ; Female ; Herpesvirus 4, Human ; Humans ; Intensive Care Units, Pediatric ; Killer Cells, Natural ; Lung Injury ; virology ; Lymphohistiocytosis, Hemophagocytic ; pathology ; virology ; Male ; Pulmonary Fibrosis ; pathology ; virology ; Retrospective Studies ; Tumor Necrosis Factor-alpha ; blood

OBJECTIVETo observe the prevention effects of patients with lung exudation and pulmonary fibrosis induced by paraquat poisoning in sodium bicarbonate (SB) with gastric lavage, atomization inhalation and intravenous injection.

METHODSTo collect 38 patients with paraquat poisoning in hospital, after poison immediately with gastric lavage of 1.5% SB, and atomization inhalation of 5% SB 10~15 ml twice daily and intravenous injection of 5% SB twice a day, continuous application of 5~7 days. and the HRCT score and liver and kidney function was performed on patients with lung after treatment. And the extraction of 38 SB patients with previously untreated with SB for comparison.

RESULTSLung HRCT average score in 72 h, 7 d, 30 d on patients with paraquat poisoning untreated with SB reached 2.87, 3.12, 2.13, HRCT display shows that the appearance of the wear glass shadow, grid shadow, honeycomb shadow, and other signs of fibrosis. Average HRCT reached 1.95, 2.20, 1.67 on patients treated with SB,signs of lung exudation and fibrosis was significantly reduced,compare two groups,there was statistically significance (P<0.01). And compared to the control group, activity of serum alanine aminotransferase (ALT) and aspartic acid transaminase (AST) decreased significantly in group of paraquat poisoning with triple application of SB, the level of serum urea nitrogen (BUN) and creatinine (Cr) significantly decreased, the difference is statistically significant (P<0.01).

CONCLUSIONThe triple application of SB can reduced the pulmonary fibrosis and effusion induced by paraquat poisoning,and protective effect on the function of liver and kidney is obvious, suggesting that the method for treatment of paraquat poisoning, prevention of paraquat lung and improve survival rate has the exact effect.

Blood Urea Nitrogen ; Creatinine ; blood ; Gastric Lavage ; Humans ; Injections, Intravenous ; Lung ; pathology ; Paraquat ; poisoning ; Pulmonary Fibrosis ; chemically induced ; therapy ; Sodium Bicarbonate ; therapeutic use ; Survival Rate

OBJECTIVETo explore the mechanism of paraquat (PQ) poisoning and to observe the changes in inflammatory cytokines in PQ-exposed rats treated in different ways.

METHODSFifty 8-week-old clean male Wistar rats were randomly divided into high-dose curcumin plus conventional treatment group, low-dose curcumin plus conventional treatment group, high-dose curcumin group, PQ poisoning group, and blank control group. On days 1, 3, 5, 7, 14, and 21 after PQ exposure, serum levels of transforming growth factor-β₁(TGF-β₁) , tumor necrosis factor-α (TNF-α) , and interleukin-6 (IL-6) were measured. The pathological changes in lung tissue were evaluated by HE staining.

RESULTSCompared with the blank control group, the high-dose curcumin plus conventional treatment group, low-dose curcumin plus conventional treatment group, high-dose curcumin group, and PQ poisoning group had significantly increased serum levels of TGF-β₁, TNF-α, and IL-6 (P<0.05) , and the three cytokines in each group reached peak levels on day 14 after exposure. Compared with the PQ poisoning group, the high-dose curcumin group had significantly reduced serum levels of TGF-β₁, TNF-α, and IL-6 (P<0.05). On day 21 after exposure, there were no significant differences in serum levels of TGF-β₁, TNF-α, and IL-6 between the high-dose curcumin plus conventional treatment group and the low-dose curcumin plus conventional treatment group (P>0.05). The HE staining revealed alveolar inflammatory changes on days 1~7 and massive pulmonary fibrosis on days 14~21 in the high-dose curcumin plus conventional treatment group, low-dose curcumin plus conventional treatment group, high-dose curcumin group, and PQ poisoning group, but the above changes were milder in the high-dose curcumin group than in the PQ poisoning group.

CONCLUSIONFor rats with PQ poisoning, curcumin can significantly reduce inflammatory response and pathological changes in lung tissue and inhibit and delay the development and progression of body injury.

Animals ; Curcumin ; pharmacology ; Cytokines ; blood ; Interleukin-6 ; blood ; Lung ; pathology ; Male ; Paraquat ; poisoning ; Pulmonary Fibrosis ; pathology ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Transforming Growth Factor beta1 ; blood ; Tumor Necrosis Factor-alpha ; blood

Coal workers' pneumoconiosis (CWP) is characterized as a chronic inflammation of the lung associated with activation of macrophages and endothelial cells in the lung. The aim of the present study was to compare the levels of serum interleukin-8 (IL-8), macrophage inflammatory protein-1alpha (MIP-alpha), and intercellular adhesion molecule-1 (ICAM-1) as biomarkers for progressive massive fibrosis (PMF) in 106 subjects (27 non-CWP and 79 CWP patients). The levels of serum IL-8 (P<0.001) and ICAM-1 (P=0.001) of subjects with PMF were higher than those of non-CWP subjects. The IL-8 levels of PMF subjects were also higher than those of simple CWP subjects (P=0.003). Among the subjects without PMF, IL-8 levels in the subjects with International Labour Organization (ILO) category II or III were higher than those in the subjects with ILO category 0 (P=0.006) and with category I (P=0.026). These results suggest that high serum levels of IL-8 and ICAM-1, which are important as neutrophil attractants and adhesion molecules, are associated with PMF.
Aged ; Anthracosis/*blood/pathology ; Biological Markers/blood ; Chemokine CCL3/*blood ; Coal Mining ; Humans ; Intercellular Adhesion Molecule-1/*blood ; Interleukin-8/*blood ; Lung/pathology ; Male ; Middle Aged ; Occupational Diseases/blood/pathology ; Pulmonary Fibrosis/*blood/pathology

Coal workers' pneumoconiosis (CWP) is characterized as a chronic inflammation of the lung associated with activation of macrophages and endothelial cells in the lung. The aim of the present study was to compare the levels of serum interleukin-8 (IL-8), macrophage inflammatory protein-1alpha (MIP-alpha), and intercellular adhesion molecule-1 (ICAM-1) as biomarkers for progressive massive fibrosis (PMF) in 106 subjects (27 non-CWP and 79 CWP patients). The levels of serum IL-8 (P<0.001) and ICAM-1 (P=0.001) of subjects with PMF were higher than those of non-CWP subjects. The IL-8 levels of PMF subjects were also higher than those of simple CWP subjects (P=0.003). Among the subjects without PMF, IL-8 levels in the subjects with International Labour Organization (ILO) category II or III were higher than those in the subjects with ILO category 0 (P=0.006) and with category I (P=0.026). These results suggest that high serum levels of IL-8 and ICAM-1, which are important as neutrophil attractants and adhesion molecules, are associated with PMF.
Aged ; Anthracosis/*blood/pathology ; Biological Markers/blood ; Chemokine CCL3/*blood ; Coal Mining ; Humans ; Intercellular Adhesion Molecule-1/*blood ; Interleukin-8/*blood ; Lung/pathology ; Male ; Middle Aged ; Occupational Diseases/blood/pathology ; Pulmonary Fibrosis/*blood/pathology

OBJECTIVETo investigate the dynamic expression of Heat shock protein 70 (Hsp70) in the lungs and plasma of rats with pulmonary fibrosis induced by silicon dioxide (SiO2).

METHODSForty-eight Wistar rats were randomly divided into the control group exposed to normal solution and group exposed to SiO2 (50 mg/ml) with intratracheal injection. Each group was divided into four subgroups. The animals of SiO2 group and control group were sacrificed and lungs were collected on the 7th, 14th and 28th days after exposure, respectively. The left lung tissues were examined with the histopathologic HE staining. The expression and localization of Hsp70 protein in the lung tissues were examined with western blot assay and immunohistochemistry, respectively. The expression levels of Hsp70 protein in the plasma were measured by ELISA.

RESULTSThe expression of Hsp70 in lung tissues of SiO2 group increased on the 7th day and reached the peak value on the 14th day then decreased, but still was significantly higher than that of the control group, the expression of Hsp70 in plasma of SiO2 group still was significantly higher than that of the control group (P < 0.05). The maximum expression level of Hsp70 in plasma of SiO2 group on the 21st day after exposure was 0.216 ± 0.027 µg/ml.

CONCLUSIONThe expression levels of Hsp70 protein in the lung tissues and plasma of the group exposed to SiO2 significantly increased, which were associated with the process of pulmonary fibrosis. It was suggested that Hsp70 protein may play an important biological role in the pulmonary fibrosis induced by SiO2.

Animals ; HSP70 Heat-Shock Proteins ; blood ; metabolism ; Lung ; metabolism ; pathology ; Male ; Pulmonary Fibrosis ; chemically induced ; metabolism ; Rats ; Rats, Wistar ; Silicon Dioxide ; toxicity

OBJECTIVETo study the roles of macrophage apoptosis, IL-1, and IL-8 in the pathogenesis of rat pulmonary fibrosis induced by silica.

METHODSForty eight male Wistar rats were divided into the 4 control groups (24 rats) and 4 experimental groups (24 rats). Rats in the control groups were treated with 1 ml normal saline by trachea instillation, whereas the rats in experimental groups were exposed 1 ml silica suspension (100 mg/ml) by trachea instillation for 1, 7, 14 and 28 days, respectively. Six rats of each group were sacrificed, then the bronchoalveolar lavage fluid and lung tissues were collected, respectively. Pulmonary inflammation, fibrosis and other pathological changes were detected with H.E. staining. Morphological changes of the early stage apoptosis in macrophages were detected with transmission electron microscope (TEM). The early apoptosis rates of macrophages in BALF were also assessed using Annexin V-FITC/PI kit. The IL-1 and IL-8 levels of serum were measured with the ELISA.

RESULTSThe apoptotic rates (11.48% +/- 0.24%, 16.03% +/- 0.68%, 15.53% +/- 1.07%, 18.92% +/- 2.70%, respectively) of macrophage in the experimental groups increased obviously with time, as compared to the controls (5.47% +/- 2.06%, 6.39% +/- 0.215, 9.07% +/- 0.61% and 8.54% +/- 0.16%, Respectively) (P < 0.05). The IL-1 levels of serum in the experimental groups were 23.64 +/- 0.84, 23.38 +/- 1.10, 22.21 +/- 0.86 and 24.29 +/- 1.31 pg/ml, respectively, which were significantly higher than those (18.52 +/- 1.23, 18.40 +/- 1.6, 17.92 +/- 2.21 and 18.53 +/- 2.64 pg/ml, respectively) in the control groups (P < 0.05) without time-effect relationship. The serum IL-8 levels on the 1st, 7th and 14th days in the experimental groups were 21.32 +/- 1.44, 21.90 +/- 2.08 and 22.00 +/- 2.80 pg/ml, respectively, which were significantly higher than those (17.69 +/- 1.09, 16.98 +/- 2.09 and 17.54 +/- 1.62 pg/ml, respectively) in the control groups (P < 0.05).

CONCLUSIONThe early macrophage apoptosis and changes of IL-1 and IL-8 may in lungs may play an important role in the development of pulmonary fibrosis induced by silica.

Animals ; Apoptosis ; drug effects ; Disease Models, Animal ; Interleukin-1 ; blood ; Interleukin-8 ; blood ; Macrophages, Alveolar ; cytology ; drug effects ; Male ; Pulmonary Fibrosis ; Rats ; Rats, Wistar ; Silicon Dioxide ; toxicity ; Silicosis ; blood ; pathology

OBJECTIVETo study the protective effects of curcumin on exaggerated extracellular matrix accumulation of pulmonary fibrosis rats.

METHODOne hundred and forty-four male Sprague-Dawley rats were randomly divided into 6 groups (24 rats in each group). Rats in the model control group, positive medicine group, and high, moderate and low curcumin groups were injected with a single dose of bleomycin by trachea, and rats in sham-model control group with same volume normal saline. One day after the injection, curcumin solution of different dosages (200, 100, 50 mg x kg(-1) x d(-1)) was respectively given to rats in the high, moderate and low curcumin group daily by gastrogavage, while equal volume of normal saline was given to those in the sham-model control group and model control group, and an equal volume of prednisone (0.56 mg x kg(-1) x d(-1)) was given to those in positive medicine control group. On the 7, 14, 28 days, 8 rats per treatment group were randomly killed, the levels of III-collagen, IV-collagen, laminin and hyaluronic acid in the serum were determined, the determination of hydroxyproline in lung homogenates was analyzed, and the lung was incised to make pathological sections which were stained with HE and Mallory.

RESULTCurcumin could decreas the levels of III-collagen, IV-collagen, laminin and hyaluronic acid in the serum, and inhihit the proliferation of fibrous tissue.

CONCLUSIONCurcumin may play its therapetuic role by leveling down the content of extracellular matrix in rats with pulmonary fibrosis induced by bleomycin.

Animals ; Bleomycin ; Body Weight ; drug effects ; Collagen Type III ; blood ; Collagen Type IV ; blood ; Curcuma ; chemistry ; Curcumin ; isolation & purification ; pharmacology ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Extracellular Matrix Proteins ; blood ; metabolism ; Hyaluronic Acid ; blood ; Hydroxyproline ; blood ; metabolism ; Laminin ; blood ; Lung ; metabolism ; pathology ; Male ; Plants, Medicinal ; chemistry ; Protective Agents ; pharmacology ; Pulmonary Fibrosis ; chemically induced ; metabolism ; pathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo explore the possible effects and mechanism of Fufang Biejiafang on a single intratracheal instillation (IT) of bleomycin-induced lung fibrosis model.

METHODSD rats were treated with a single IT dose of bleomycin or control saline. Chinese medicine group were poured into the stomach after the first day of operation with high dosage, middle dosage and low dosage. On days 7, 14 and 28 following IT bleomycin or saline, 4 mL blood were taken from the abdominal aorta for arterial blood gas analysis. The left lung was fixed for routine light microscopic examination. Bronchoalveolar lavage fluid (BALF) from the right lung was tested the activity of pulmonary surfactant (PS) by the Whihelmy Film Balance, then the right lung was frozen immediately in liquid nitrogen for determination of hydroxyproline concentration.

RESULTModel rats had obviously changes of body weight and hypoxemia and dysfunction of PS on days 7 and improved on days 14. Compared with three dose groups, the middle dose group some degreely improved and PS function. It ameliorate fibrosis because of inhibition of inflammation.

CONCLUSION(1) PS dysfunction resulted in hypoxemia after bleomycin injured alveolar type II (AT II). Fufang biejiafang-middle dose-group ameliorate hypoxemia by remission AT-II injury. (2) Fufang biejiafang may inhibit exudation inflammation and ameliorate fibrosis.

Animals ; Bleomycin ; Blood Gas Analysis ; Bronchoalveolar Lavage Fluid ; cytology ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Male ; Materia Medica ; isolation & purification ; pharmacology ; Paeonia ; chemistry ; Panax ; chemistry ; Plants, Medicinal ; chemistry ; Protective Agents ; pharmacology ; Pulmonary Fibrosis ; chemically induced ; metabolism ; pathology ; Pulmonary Surfactants ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Turtles