Pretreatment of a matrix metalloproteases inhibitor and aprotinin attenuated the development of acute pancreatitis-induced lung injury in rat model.

OBJECTIVE: Acute lung injury (ALI) is one of the most common extra-pancreatic complications of acute pancreatitis. In this study, we examined the protective effect of protease inhibitor aprotinin and a matrix metalloproteinase inhibitor (MMPi) on pulmonary inflammation in rats with severe pancreatitis-associated ALI. METHOD: A rat model of acute pancreatitis (AP) was established by injecting sodium glycodeoxycholate (GDOC) into the pancreatic duct. Pharmacological interventions included pretreatment with a protease inhibitor aprotinin (10mg/kg) and a matrix metalloproteinase inhibitor (MMPi, 100g/kg). The extent of pancreatic and lung injury and systemic inflammation was assessed by examinations of blood, bronchoalveolar lavage (BAL), and lung tissue. Pancreatic or lung tissue edema was evaluated by tissue water content. Pulmonary arterial pressure and alveolar-capillary membrane permeability were evaluated post-injury via a catheter inserted into the pulmonary artery in an isolated, perfused lung model. RESULTS: Pre-treatment with aprotinin or MMPi significantly decreased amylase and lactate dehydrogenase (LDH), and the wet/dry weight ratio of the lung and pancreas in AP rats. Compared to the GDOC alone group, administration of aprotinin or MMPi prevented pancreatitis-induced IL-6 increases in the lung. Similarly, treatment with aprotinin or MMPi significantly decreased the accumulation of white blood cells, oxygen radicals, nitrite/nitrates in both blood and BAL, and markedly reduced lung permeability. CONCLUSION: Pretreatment with either aprotinin or MMPi attenuated the systemic inflammation and reduced the severity of lung and pancreas injuries. In short, our study demonstrated that inhibition of protease may be therapeutic to pulmonary inflammation in this GDOC-induced AP model.

Optimizing Survival of Patients With Marginally Operable Stage IIIA Non-Small-Cell Lung Cancer Receiving Chemoradiotherapy With or Without Surgery.

BACKGROUND: For marginally operable stage IIIA non-small-cell lung cancer (NSCLC), surgery might not be done as planned after neoadjuvant concurrent chemoradiotherapy (CCRT) for reasons (unresectable or medically inoperable conditions, or patient refusal). This study aims to investigate the outcomes of a phased CCRT protocol established to maximize the operability of marginally operable stage IIIA NSCLC and to care for reassessed inoperable patients, in comparison with continuous-course definitive CCRT. MATERIALS AND METHODS: Forty-seven patients with marginally operable stage IIIA NSCLC receiving CCRT were included. Twenty-eight patients were treated with our phased CCRT protocol, including neoadjuvant CCRT followed by surgery (group A, n = 16) or, for reassessed inoperable patients, maintenance chemotherapy and split-course CCRT boost (group B, n = 12). The other 19 were treated with continuous-course definitive CCRT (group C). Overall survival (OS) and progression-free survival (PFS) were analyzed. RESULTS: Among all, median OS and PFS were 35.6 and 12.8 months, respectively (median follow-up, 22.3 months). The median OS of group A (not reached) was better than that of group B (34.4 months) and group C (15.2 months) (P = .009). On multivariate analysis, performance status 0 to 1 (hazard ratio [HR], 0.026; P < .001), adenocarcinoma (HR, 0.156; P = .003), and group A (HR, 0.199; P = .033) were independent prognostic factors. The OS of group B (HR, 0.450; 95% confidence interval, 0.118-1.717; P = .243) was not statistically different from that of group C. CONCLUSIONS: For marginally operable stage IIIA NSCLC, our phased CCRT strategy may optimize survival by maximizing operability and maintain an acceptable survival for reassessed inoperable patients by split-course CCRT boost following maintenance chemotherapy.

Risk of Stroke in Patients With Spontaneous Pneumothorax: A Nationwide, Population-Based Study.

The association between spontaneous pneumothorax (SP) and stroke has not been reported, and this study aimed to explore this association. We used the National Health Insurance Research Database for conducting a nationwide, population-based, retrospective cohort study of patients newly hospitalized for SP from 2000 to 2010. A total of 2541 patients with newly diagnosed SP were included and compared with patients without SP. We observed that patients with SP were at higher risk for developing stroke, with an adjusted hazard ratio (HR) of 1.56. In addition, these patients had a significantly higher risk of hemorrhagic stroke (adjusted HR = 2.22) than of ischemic stroke (adjusted HR = 1.48). The risk of stroke was the highest in the initial 4 months after hospitalization for SP (adjusted HR = 3.41, 95% confidence interval = 1.98-5.87). In conclusion, our study revealed a correlation between stroke and a history of SP, and the risk of stroke after SP was time sensitive.

Mechanisms of human lymphotoxin beta receptor activation on upregulation of CCL5/RANTES production.

Human lymphotoxin-ß receptor (LTßR), a member of the tumor necrosis factor receptor superfamily, plays an essential role in secondary lymphoid organ development, host defense, chemokine secretion, and apoptosis. In our study, LTßR activations by different stimulations were all found to induce RANTES secretion. Overexpression of LTßR or stimulation LTßR by ligands or agonistic antibody in human lung epithelial cells induced RANTES secretion However, the regulatory mechanism and the signaling cascade have not been fully elucidated. Therefore, the aim of this study was to elucidate the mechanism underlying LTßR-mediated RANTES production. Our study indicated that activation of JNK and ERK was important for the regulation of RANTES secretion. In addition, dominant negative mutants of ASK1, TAK1, and MEKK1 inhibited LTßR-induced RANTES expression. The dominant negative mutants of TRAF2, 3, and 5 also inhibited LTßR-mediated RANTES secretion. Chromatin immunoprecipitation analysis showed that LTßR activation induced the binding of c-Jun and NF-κB to the RANTES promoter. The results of this study show that LTßR activates ASK1, TAK1, and MEKK1 cascades via TRAF2, 3, and 5, resulting in the activation of JNK and ERK, which promotes the binding of c-Jun and NF-κB to the RANTES promoter, thereby increasing RANTES expression and secretion.

Crystal amphetamine smoking-induced acute eosinophilic pneumonia and diffuse alveolar damage: a case report and literature review.

Eosinophilic pneumonia (EP) is a disease characterized by prominent infiltration of lung structures by eosinophils. The lung interstitium is infiltrated by eosinophils, and essentially the alveolar spaces are filled with eosinophils and a fibrinous exudate, with conservation of the global architecture of the lung. Diagnosis of EP relies on pathological demonstration of alveolar eosinophilia along with characteristic clinical manifestations of nonproductive cough, dyspnea, chest pain and/or unique imaging features. EP may be categorized according to the origin: EP of undetermined origin may overlap with well-individualized syndromes, while EP with a definite cause are mainly due to infections or drug abuse. Here, we report a case of an amphetamine abuser who developed acute EP and acute respiratory distress syndrome after amphetamine inhalation. Related studies on the pathogenesis of stimulant-related lung injury and treatment strategies are also discussed.

Clinical and pathological features of fat embolism with acute respiratory distress syndrome.

FES (fat embolism syndrome) is a clinical problem, and, although ARDS (acute respiratory distress syndrome) has been considered as a serious complication of FES, the pathogenesis of ARDS associated with FES remains unclear. In the present study, we investigated the clinical manifestations, and biochemical and pathophysiological changes, in subjects associated with FES and ARDS, to elucidate the possible mechanisms involved in this disorder. A total of eight patients with FES were studied, and arterial blood pH, PaO(2) (arterial partial pressure of O(2)), PaCO(2) (arterial partial pressure of CO(2)), biochemical and pathophysiological data were obtained. These subjects suffered from crash injuries and developed FES associated with ARDS, and each died within 2 h after admission. In the subjects, chest radiography revealed that the lungs were clear on admission, and pulmonary infiltration was observed within 2 h of admission. Arterial blood pH and PaO(2) declined, whereas PaCO(2) increased. Plasma PLA(2) (phospholipase A(2)), nitrate/nitrite, methylguanidine, TNF-alpha (tumour necrosis factor-alpha), IL-1beta (interleukin-1beta) and IL-10 (interleukin-10) were significantly elevated. Pathological examinations revealed alveolar oedema and haemorrhage with multiple fat droplet depositions and fibrin thrombi. Fat droplets were also found in the arterioles and/or capillaries in the lung, kidney and brain. Immunohistochemical staining identified iNOS (inducible nitric oxide synthase) in alveolar macrophages. In conclusion, our clinical analysis suggests that PLA(2), NO, free radicals and pro-inflammatory cytokines are involved in the pathogenesis of ARDS associated with FES. The major source of NO is the alveolar macrophages.

Increased nitric oxide production accompanies blunted hypoxic pulmonary vasoconstriction in hyperoxic rat lung.

Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in > 90% F1O2 for 60 h prior to experiments. After baseline in vitro analysis, the rats underwent isolated, perfused lung experiments. Two consecutive hypoxic challenges (10 min each) were administered with the administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in between. We measured intravascular NO production, pulmonary arterial pressure, and protein expression of eNOS and iNOS by immunohistochemistry. We found that hyperoxia rats exhibited increased baseline NO production (P < 0.001) and blunted HPV response (P < 0.001) during hypoxic challenges compared to normoxia rats. We also detected a temporal association between the attenuation in HPV and increased NO production level with a negative pre-L-NAME correlation between HPV and NO (R = 0.52, P < 0.05). After L-NAME administration, a second hypoxic challenge restored the HPV response in the hyperoxic group. There were increased protein expression of eNOS (12.6 +/- 3.1-fold, n = 3) (X200) and iNOS (8.1 +/- 2.6-fold, n = 3) (X200) in the hyperoxia group. We conclude that hyperoxia increases the protein expression of eNOS and iNOS with a subsequent increased release of endogenous NO, which attenuates the HPV response.

Static inflation attenuates ischemia/reperfusion injury in an isolated rat lung in situ.

STUDY OBJECTIVES: Ischemia (I)/reperfusion (R) lung injury is an important clinical issue in lung transplantation. In the present study, we observed the effects of lung static inflation, different perfusates, and ventilatory gas with nitrogen or oxygen on the I/R-induced pulmonary damage. DESIGN AND SETTING: A total of 96 male Sprague-Dawley rats were used. The lung was isolated in situ. METHODS: In an isolated lung, the capillary filtration coefficient (Kfc), lung weight gain (LWG), lung weight (LW)/body weight (BW) ratio, and protein concentration in BAL fluid (PCBAL) were measured or calculated to evaluate the degree of lung injury. Histologic examinations with hematoxylin-eosin staining were performed. RESULTS: I/R caused lung injury, as reflected by increases in Kfc, LWG, LW/BW, and PCBAL. The histopathologic picture revealed the presence of hyaline membrane formation and the infiltration of inflammatory cells. These values were significantly attenuated by static lung inflation. The I/R lung damage appeared to be less in the lung perfused with whole blood than in the lung perfused with an isotonic solution. Therapy with ventilatory air (ie, nitrogen or oxygen) did not alter the I/R lung damage. CONCLUSIONS: The data suggest that lung inflation is protective to I/R injury, irrespective of the type of ventilatory air used for treatment. The preservation of the lung for transplantation is better kept at a static inflation state and perfused with whole blood instead of an isotonic physiologic solution.