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Neutrophils are considered to play a central role in ventilator-induced lung injury (VILI). However, the pulmonary consequences of neutrophil accumulation have not been fully elucidated. Matrix metalloproteinase-9 (MMP-9) had been postulated to participate in neutrophil transmigration. The purpose of this study was to investigate the role of MMP-9 in the neutrophilic inflammation of VILI. Male Sprague-Dawley rats were divided into three groups: l) low tidal volume (LVT), 7 ml/kg of tidal volume ([V.sub.T]); 2) high tidal volume (HVT), 30 ml/kg of [V.sub.T]; and 3) HVT with MMP inhibitor (HVT + MMPI). As a MMPI, CMT-3 was administered daily from 3 days before mechanical ventilation. Degree of VILI was assessed by wet-to-dry weight ratio and acute lung injury (ALI) scores. Neutrophilic inflammation was determined from the neutrophil count in the lung tissue and myeloperoxidase (MPO) activity in the bronchoalveolar lavage fluid (BALF). MMP-9 expression and activity were examined by immunohistochemical staining and gelatinase zymography, respectively. The wet-to-dry weight ratio, ALI score, neutrophil infiltration, and MPO activity were increased significantly in the HVT group. However, in the HVT + MMPI group, pretreatment with MMPI decreased significantly the degree of VILI, as well as neutrophil infiltration and MPO activity. These changes correlated significantly with MMP-9 immunoreactivity and MMP-9 activity. Most outcomes were significantly worse in the HVT + MMPI group compared with the LVT group. In conclusion, VILI mediated by neutrophilic inflammation is closely related to MMP-9 expression and activity. The inhibition of MMP-9 protects against the development of VILI through the downregulation of neutrophil-mediated inflammation. metalloproteinase inhibitor; neutrophil; mechanical ventilators

The main etiologic factor for chronic bronchitis is cigarette smoke. Exposure to cigarette smoke is reported to induce goblet cell hyperplasia and mucus production. Mucin synthesis in airways has been reported to be regulated by the EGFR system. Peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]) is a member of the ligand-activated nuclear receptor superfamily. PPAR-[gamma] is implicated in anti-inflammatory responses, but mechanisms underlying these varied roles remain ill-defined. Recently, reports have shown that upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) might be one of the mechanisms through which PPAR-[gamma] agonists exert their anti-inflammatory actions. However, no data are available on the role of PPAR-[gamma] in smoke-induced mucin production. In this study, we investigated the effect of PPAR-[gamma] agonist (rosiglitazone) on smoke-induced mucin production in NCI-H292 cells. Exposure to cigarette smoke causes a significant decrease in PTEN expression and increases dose-dependent EGFR-specific tyrosine phosphorylation, resulting in MUC5AC mucin production in NCI-H292 cells. PPAR-[gamma] agonists or specific inhibitors of phosphoinositide 3-kinase exert inhibition of cigarette smoke-induced mucin production, with the upregulation of PTEN signaling and downregulation of Akt expression. This study demonstrates that PPAR-[gamma] agonist functions as a regulator of epithelial cell inflammation that may result in reduction of mucin-producing cells in airway epithelium. rosiglitazone; epidermal growth factor receptor; phosphatase and tensin homolog deleted on chromosome 10; smoking

Bacterial infections of the lung are known to induce inflammatory responses, which lead to mucus hypersecretion. Moreover, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and its activation. Furthermore, matrix metalloproteinases (MMPs), especially MMP-9, have been reported to promote the transmigration of activated neutrophils. In this study, we investigated the associations between lipopolysaccharide (LPS)-induced goblet cell (GC) metaplasia and EGFR expression and the effects of MMP inhibitor (MMPI). Various concentrations of LPS were instilled into the tracheas of pathogen-free Sprague-Dawley rats, and airways were examined at different times after LPS instillation. To examine the role of MMP-9, we treated rats 3 days before LPS instillation and daily thereafter with MMPI. Neutrophilic infiltration, Alcian blue/periodic acid-Schiff (AB/PAS) staining, and immunohistochemical staining for MUC5AC, EGFR, and MMP-9 were performed. The instillation of LPS increased AB/PAS and MUC5AC staining in time- and dose-dependent manners, and treatment with MMPI significantly prevented GC metaplasia. The instillation of LPS into the trachea also induced neutrophilic infiltration and EGFR and MMP-9 expression in the airway epithelium, and MMPI was found to significantly prevent neutrophil recruitment, GC metaplasia, and EGFR and MMP-9 expression. This study demonstrates that the MMP-9 and EGFR cascades are associated with LPS-induced mucus hypersecretion. lipopolysaccharide; mucus hypersecretion

Background: It is important to assess the prognosis of patients with chronic obstructive pulmonary disease (COPD) and acute exacerbation of COPD (AECOPD). Recently, it was suggested that diffusing capacity of the lung for carbon monoxide (DLCO) should be added to multidimensional tools for assessing COPD. This study aimed to compare the DLCO and forced expiratory volume in one second (FEV1) to identify better prognostic factors for admitted patients with AECOPD.Methods: We retrospectively analyzed 342 patients with AECOPD receiving inpatient treatment. We classified 342 severe AECOPD patients by severity of DLCO and FEV1 (≤ vs. > 50% predicted). We tested the association of FEV1 and DLCO with the following outcomes: in-hospital mortality, need for mechanical ventilation, need for intensive care unit (ICU) care. We analyzed the prognostic factors by multivariate analysis using logistic regression. In addition, we conducted a correlation analysis and receiver operating characteristic (ROC) curve analysis.Results: In multivariate analyses, DLCO was associated with mortality (odds ratio = 4.408; 95% CI 1.070-18.167; P = 0.040) and need for mechanical ventilation (odds ratio = 2.855; 95% CI 1.216-6.704; P = 0.016) and ICU care (odds ratios = 2.685; 95% CI 1.290-5.590; P = 0.008). However, there was no statistically significant difference in mortality rate when using FEV1 classification (P = 0.075). In multivariate linear regression analyses, DLCO (B = - 0.542 ± 0.121, P < 0.001) and FEV1 (B = - 0.106 ± 0.106, P = 0.006) were negatively associated with length of hospital stay. In addition, DLCO showed better predictive ability than FEV1 in ROC curve analysis. The area under the curve (AUC) of DLCO was greater than 0.68 for all prognostic factors, and in contrast, the AUC of FEV1 was less than 0.68.Conclusion: DLCO was likely to be as good as or better prognostic marker than FEV1 in severe AECOPD. [ABSTRACT FROM AUTHOR]

Background: In patients with sepsis, an inflammatory response can lead to destruction of the glycocalyx. These alterations cause the progression of organ dysfunction. Destruction of the glycocalyx can also occur in chronic hyperglycemia. Glycated hemoglobin (HbA1c) is a reliable marker of premorbid hyperglycemia. We investigated the association between HbA1c level at admission and the degree of organ dysfunction progression 72 hours after admission and ICU mortality. Methods and findings: This study was a retrospective observational study. Logistic regression and correlation analyses were performed to evaluate the association between the HbA1c level and the degree of organ dysfunction progression 72 hours after ICU admission. We applied survival analysis to examine the association between HbA1c level and ICU mortality. A total of 90 patients were included in this study. The association between HbA1c level and degree of organ dysfunction progression was significant (r = 0.320; P = 0.002). Multivariable logistic regression analysis showed that high HbA1c level (≥6.5%) (OR, 2.98; 95% CI, 1.033–8.567; P = 0.043) were significant, independent predictors of severe organ dysfunction progression. Patients with an HbA1c level ≥6.5% exhibited significantly greater liver and kidney dysfunction progression 72 hours after ICU admission compared with those with an HbA1c level <6.5%. Kaplan-Meier analysis showed that the survival period was significantly shorter in patients with an HbA1c level ≥6.5% than in those with an HbA1c level <6.5% (P < 0.001). Multivariable Cox proportional hazard analysis showed that HbA1c level ≥6.5% (HR, 3.49; 95% CI, 1.802–6.760; P <0.001) were significant, independent predictors of ICU mortality. Conclusions: In patients with sepsis, the HbA1c level at ICU admission is associated with progression of organ dysfunction 72 hours later and with ICU mortality. It may be important to assess HbA1c level at ICU admission because it may be a predictor of ICU outcome. For patients with a high HbA1c level (≥6.5%), greater attention should be paid to the possibility of organ dysfunction progression. [ABSTRACT FROM AUTHOR]