Pirfenidone alleviates lipopolysaccharide-induced lung injury by accentuating BAP31 regulation of ER stress and mitochondrial injury.

Pirfenidone has been widely used in the treatment of idiopathic pulmonary fibrosis (IPF). However, the role of pirfenidone in LPS-induced acute lung injury (ALI) remains unclear. This study aims to investigate the protective effects of pirfenidone in ALI and to explore its underlying mechanism. Pirfenidone clearly reduces LPS-triggered ALI as indicated by significant pathological alterations, reduced oxidative stress and inflammatory responses in vivo. Furthermore, pirfenidone also blocks apoptosis of LPS-induced alveolar epithelial type II (ATII) cells through inhibition of endoplasmic reticulum (ER) stress and mitochondrial injury in vivo and in vitro. A lower expression level of BAP31, an ER transmembrane protein, was found to be associated with ALI followed LPS challenge. The reintroduction of BAP31 blunted LPS induced ER stress and mitochondrial damage and therefore alleviated ATII cell apoptosis, which correlated with pirfenidone treatment. Knockdown of BAP31 expression in pirfenidone treated ATII cells re-activated ER stress, mitochondrial damage and followed cellular apoptosis. In summary, this study confirms the beneficial effect of pirfenidone on ER stress and mitochondrial dysfunction mediated apoptosis via upregulation of BAP31. Our results demonstrated that pirfenidone may be considered as a potential agent for the treatment of ALI in the future.

Genetic diversity of antigen 38 kDa in Mycobacterium tuberculosis strains from China.

We used 335 Mycobacterium tuberculosis strains from 2010 National Epidemiologic Survey for TB in China and performed comparative sequence analysis of 38 kDa gene after amplification. From the results, we found that there were 5.07% M.tuberculosis strains that demonstrated genetic diversity of 38 kDa in China, and 2.99% strains showed polymorphism of the 38 kDa antigen, and this may be the reason for changes in the antigen produced, which may in turn cause alterations of related functions, thereby allowing immune evasion.

Association of matrix metalloproteinase family gene polymorphisms with lung cancer risk: logistic regression and generalized odds of published data.

Many studies have reported the association between the matrix metalloproteinase (MMP) polymorphisms and lung cancer susceptibility, but the results were inconclusive. We conducted a meta-analysis, using a comprehensive strategy based on the logistic regression and a model-free approach, to derive a more precise estimation of the relationship between MMP1, MMP2, MMP9 and MMP13 polymorphisms with lung cancer risk. A total of 22 case-control studies including 8202 cases and 7578 controls were included in this meta-analysis. For MMP1-1607 1G/2G, increased lung cancer risk was found among Asians in additive model(OR = 1.34, 95%CI:1.18-1.53) and with model-free approach(ORG = 1.41, 95%CI:1.21-1.65). For MMP2-1306 C/T and -735 C/T, based on the model-free approach, a significantly reduced risk was found in Asians(MMP2-1306 C/T:ORG = 0.49,95%CI:0.42-0.57; MMP2-735 C/T: ORG = 0.71, 95%CI:0.61-0.84). For MMP9-1562 C/T, a significantly increased risk was found among Asians(OR = 2.73, 95%CI:1.74-4.27) with model-free approach. For MMP13-77A/G, there was no association between this polymorphism and lung cancer risk in the recessive model(OR = 1.02, 95%CI:0.83-1.26) and with the model-free approach(ORG = 0.95, 95%CI:0.76-1.17). Therefore, this meta-analysis suggests that the MMP1-1607 1G/2G, MMP2-1306 C/T, MMP2-735 C/T, MMP9 -1562 C/T polymorphisms were risk factors for lung cancer among Asians, while MMP13 -77A/G polymorphism was not associated with lung cancer risk.

Time course changes of oxidative stress and inflammation in hyperoxia-induced acute lung injury in rats.

OBJECTIVES: Therapies with high levels of oxygen are commonly used in the management of critical care. However, prolonged exposure to hyperoxia can cause acute lung injury. Although oxidative stress and inflammation are purported to play an important role in the pathogenesis of acute lung injury, the exact mechanisms are still less known in the hyperoxic acute lung injury (HALI). MATERIALS AND METHODS: In this study, we investigated the time course changes of oxidative stress and inflammation in lung tissues of rats exposed to >95% oxygen for 12-60 hr. RESULTS: We found that at 12 hr after hyperoxia challenge, the activities of superoxide dismutase and glutathione peroxidase were significantly reduced with remarkably increased lipid peroxidation. At 12 hr, NF-κB p65 expression was also upregulated, but Iκ-Bα expression showed a remarkable decline. Significant production of inflammatory mediators, e.g, interleukin-1ß, occurred 24 hr after hyperoxia exposure. In addition, the expression of intracellular adhesion molecule 1 expression and the activity of myeloperoxidase were significantly increased at 24 hr with a peak at 48 hr. CONCLUSION: Our data support that hyperoxia-induced oxidative damage and NF-κB pathway activation implicate in the early phase of HALI pathogenesis.

Heme oxygenase-1 system, inflammation and ventilator-induced lung injury.

Mechanical ventilation is an indispensable supportive intervention for acute respiratory failure. However, mechanical ventilation can provoke ventilator-induced lung injury, which remains one of the major causes of morbidity and mortality in critically ill patients. Excessive inflammatory response characterized by infiltration of inflammatory cells and overproduction of inflammatory mediators contributes to the pathogenesis of ventilator-induced lung injury. At present, apart from the protective ventilation strategy, no other pharmacological intervention is available to attenuate ventilator-induced lung injury. Heme oxygenase-1 (HO-1) is the inducible isoform of the first and rate-limiting enzyme which degrades heme into carbon monoxide, ferritin and bilirubin. Accumulating evidence suggests that HO-1 system may function as a crucial negative regulator in the modulation of inflammatory process. This anti-inflammatory action of HO-1 is mediated essentially by the regulation of the key cells involved in inflammation and restoration of the balance between pro-inflammatory and anti-inflammatory mediators. Therefore, HO-1 system represents a promising therapeutic target for intervention of ventilator-induced lung injury.

Protective effects of hemin in an experimental model of ventilator-induced lung injury.

Mechanical ventilation is an indispensable life-support modality for critically ill patients with acute lung injury or acute respiratory distress syndrome. Unfortunately, mechanical ventilation even the protective ventilation strategies may evoke ventilator-induced lung injury. Heme oxygenase-1 (HO-1) has recently exhibited anti-inflammatory and anti-oxidative properties in vitro and in vivo. The effect of HO-1 in ventilator-induced lung injury has not been fully characterized. In this study, rabbits were subjected to high tidal volume ventilation to induce ventilator-induced lung injury, which was confirmed by histopathological alterations, increased bronchoalveolar lavage fluid protein content and lung wet-to-dry ratio. In contrast to the level of HO-1 expression in high tidal volume group, pretreatment with hemin, an inducer of HO-1, further up-regulated HO-1 expression. At the same time, these lung injury indexes were attenuated markedly. This pulmonary protection was accompanied by a decrease in bronchoalveolar lavage fluid neutrophil count and in lung myeloperoxidase activity. Besides, pretreatment with hemin prohibited the production of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-8, and up-regulated the level of anti-inflammatory cytokine interleukin (IL)-10 in bronchoalveolar lavage fluid. Furthermore, a decreased malondialdehyde activity, a marker of oxidative stress and a robust increase in total antioxidant capacity were observed in hemin-treated animals. Our findings suggest that HO-1 up-regulation by hemin plays a protective role in ventilator-induced lung injury by suppression inflammatory process and oxidative stress.

[Comparison of SmartCare and spontaneous breathing trials for weaning old patients with chronic obstructive pulmonary diseases].

OBJECTIVE: To compare the outcome of the SmartCare and spontaneous breathing trials (SBT) for weaning old patients with chronic obstructive pulmonary diseases (COPD). METHODS: Thirty-eight COPD patients were enrolled in Department of Respiratory Medicine on the South Building, General Hospital of People's Liberation Army from January, 2003 to April, 2005. They mechanically ventilated for at least 3 d (age: 70 - 91 year, average: 83.3 +/- 4.3), randomly assigned to receive SmartCare (SC group, n = 13) or SBT (SBT group, n = 25). All patients were considered clinically and biologically stable, and therefore ready to be weaned from mechanical ventilation. In SC group, patients were ventilated with an inspiratory pressure (IPAP) support adjusted to achieve pH value > or = 7.35, saturation of oxygen in arterial blood (SaO2) > or = 90%, respiratory frequency (RR) > or = 10 and < or = 30 breaths/min, and fraction of inspired oxygen (FiO2) < or = 45%. In SBT group, the patients were placed in a weaning protocol utilizing increasing duration of spontaneous breathing. The following data were recorded at weaning: the acute physiology and chronic health evaluation II (APACHE II) score, arterial blood gases under mechanical ventilation, serum calcium, magnesium, and phosphorus, the days of ventilation before weaning and the duration of weaning. The patients of both groups were considered as successfully weaned when they were able to tolerate at least 48 consecutive hours of spontaneous breathing. Failure was defined in a patient who died during the weaning process or who still needed mechanical ventilation after at least 40 consecutive days of weaning. RESULTS: No significant differences were found between the groups at the onset of weaning from mechanical ventilation regarding APACHE II, serum albumin, calcium, magnesium, phosphorus, partial pressure of carbon dioxide in arterial blood (PaCO2), and the days of mechanical ventilation (t = 0.834, 0.696, 1.384, 0.682, 0.467, 0.816, 0.384, all P > 0.05). The pH value of the SBT group (7.45 +/- 0.05) was higher than the SC group (7.40 +/- 0.04, t = 3.263, P < 0.05). Although patients in the SC group spent less time in weaning than those in the SBT group, the difference was not significant [(8.54 +/- 2.09), (13.32 +/- 2.19) d for the SC and SBT groups, respectively, t = 1.320, P = 0.251]. The 7-d weaning success rate was greater in the SC group than the SBT group (77%, 40%, chi(2) = 4.677, P = 0.031). No significant difference was found in 14-d weaning success rate (77%, 64% in the SC and SBT groups, chi(2) = 0.661, P = 0.416). Fewer arterial blood analyses were performed in the SC group (3.5 +/- 3.1, 6.6 +/- 3.7, t = 2.710, P = 0.011). CONCLUSION: The SmartCare is better than SBT in weaning patients with COPD within 7 days.

[Ventilator-associated pneumonia caused by Pneumocystis carinii in the non-human immunodeficiency virus infection: a report of 5 cases].

OBJECTIVE: To comprehend ventilator-associated pneumonia (VAP) caused by pneumocystis carinii (P. carinii-VAP) in the non-human immunodeficiency virus (HIV) infected patients. METHODS: The clinical data of 5 patients with P. carinii-VAP in the non-HIV patients from 2000 to 2003 in our hospital were reviewed. RESULTS: Five male patients, aged 71 - 93, had severe predisposing diseases and respiratory failure induced by lung infection. All patients were treated with mechanical ventilation and multiple antibiotics and had recurrent VAP. Fever was present in all patients together with respiratory symptoms. Moist rales were noted in four of them. X-ray showed diffuse patchy shadows in 4 patients, extensive densities in 1 cases, reticular infiltrations in 2 cases, and pleural effusion in 2 cases. Sputum P. carinii was found by smear staining in 4 cases as well as a positive PC PCR. The remaining case only showed a positive PC PCR. Four patients were cured after treatment with SMZco, but one patient died. CONCLUSION: P. carinii-VAP could occur during prolonged mechanical ventilation for severe respiratory diseases, particularly in aged patients with advanced cancer or treated with glucocorticoids and broad spectrum antibiotics.

[Value of blinded sampling methods in the pathogenic diagnosis of ventilator-associated pneumonia].

OBJECTIVE: To evaluate the diagnostic value of blinded protected specimen brush and quantitative culture (BPSB-QC) in the pathogenic diagnosis of ventilator-associated pneumonia (VAP). METHODS: A prospective, self-controlled clinical trial was conducted during a 36-month period. QC of paired samples of BPSB and PSB via a fiberoptic bronchoscopy (FOB- PSB) in a total of 54 patients during 125 suspected episodes of VAP was compared. The sensitivity and accuracy, as well as the concordance between BPSB-QC and FOB-PSB-QC result in 48 patients with 106 episodes of VAP were assessed. Both BPSB-QC and FOB-PSB-QC greater than 103 cfu/ml (positive cutoff) was considered diagnostic of VAP. RESULTS: Forty-eight patients with 106 episodes were considered to have VAP (84.8%). The accuracy of BPSB-QC and FOB-PSB-QC were 80.8% (101/125) and 83.2% (104/125), respectively. The rate of complete concordant results was high (75.2%) for BPSB-QC and FOB-PSB-QC. The pathogenic diagnostic agreement between the two techniques was 84.8% (106/125). There were no significant differences with regard to site of pneumonia and positive diagnostic rate between the two techniques. CONCLUSION: BPSB-QC has similar accuracy and same feasibility compared with FOB-PSB-QC which was commonly primarily used in the pathogenic diagnosis of VAP, and that its use is substantially simpler, safe and cost saving, especially when FOB technique is not available.

[Protective effect of N-acetylcysteine on acute lung injury caused by exposure to rocket liquid propellant].

OBJECTIVE: To investigate the protective effect and its mechanisms of N-acetylcysteine (NAC) on acute lung injury (ALI) caused by exposure to high concentration rocket liquid propellants asymmetrical dimethylhydrazine (UDMH) and dinitrogen tetroxide (N(2)O(4)). METHODS: Forty-two rats were randomly divided into three groups: the control group, the exposure group and the exposure plus the treatment group (NAC group). The rats of the latter two groups were exposed to UDMH 0.98 mg/L for 10 minutes and then N(2)O(4) 0.19 mg/L for another 10 minutes. After the exposure, the NAC group rats received immediately 150 mg/kg of NAC intravenously, and rein forced by intraperitoneal injection of NAC with a dose of 50 mg/kg 3 hours after the intravenous injection. The rats of other group were treated with saline in equal volume. All rats were killed after 6 hours. The lung wet to dry ratio (W/D ), the contents of lactate dehydrogenase (LDH) and total protein in bronchoalveolar lavage fluid (BALF), the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissue, and the malondialdehyde (MDA) of plasma were measured. Pathological examination was performed. RESULTS: The lung W/D ratio, the LDH and total protein in BALF, and the MDA of plasma were increased in the exposure group, while the activities of SOD and GSH-Px in lung tissue were decreased. The histopathology of the rats of exposure groups showed that there was exudation within alveolar spaces and prominent interstitial thickening of septa. In the NAC group, the values of the above findings were lowered, and the degree of lung injury was alleviated in histopathology. The lung W/D were negatively correlated with the activities of SOD and GSH-Px in lung tissue, and the correlation coefficient were-0662 (P<0.01) and -0707(P<0.01) respectively. CONCLUSION: The administration of NAC appears to attenuate the injury to the lung after an exposure to UDMH and N(2)O(4) in high concentration, and the antioxidant activity of NAC may be responsible for the protective effect.