Relationship Between Visceral Metastases and Survival in Patients with Metastasis-related Spinal Cord Compression.

OBJECTIVE: To investigate whether visceral metastases have a significant impact on survival in patients with metastasis-related spinal cord compression (MSCC), and to determine the difference in prognosis between patients with and without visceral metastases. METHODS: Three institutional databases were searched to identify all patients who had undergone spinal surgery for spinal metastases between March 2002 and June 2010. Data on patient characteristics including pre- and post-operative medical conditions, were collected from medical records or by telephone follow-up. Survival data were obtained either from medical records or by searching a governmental cancer registry. RESULTS: The mean age of study patients was 59.6 ± 10.5 years (range, 18-84 years), of whom 102 were male and 67 female. The median and mean postoperative survival times were 7.0 ± 0.5 (95% CI 6.0-8.0) months and 12.6 ± 1.2 (95% CI 10.1-15.0) months, respectively, in all patients, being 5.0 ± 0.5 (95% CI 4.0-6.0) months and 10.8 ± 2.4 (95% CI 6.1-15.5) months, respectively, for patients with visceral metastases and 7.0 ± 0.8 (95% CI 5.4-8.6) months and 13.0 ± 1.4 (95%CI 10.3-15.6) months, respectively, for patients without visceral metastases (P = 0.87). These survival times did not differ significantly between groups. Multivariate Cox proportional hazard regressions showed that visceral metastases had no statistically significant association with survival (P = 0.277), whereas rate of growth of primary tumor (P = 0.003), preoperative Karnofsky performance status (KPS) (P < 0.001), change in KPS (P < 0.001), and Frankel grade (P = 0.091) were independent prognostic factors in the whole cohort (P = 0.005). Changes in KPS (P = 0.001) and major complications (P = 0.003) were significantly associated with survival in patients with visceral metastases, whereas rate of growth of primary tumor (P = 0.016), change in KPS (P = 0.001), and preoperative KPS (P < 0.001) were significantly associated with survival in patients without visceral metastases. CONCLUSIONS: Visceral metastases do not appear to predict the prognosis of patients with MSCC; thus, more aggressive surgery should be considered in patients with MSCC who have visceral metastases. Additionally, prognostic factors differ according to visceral metastases status in these patients.

BML-111 suppresses TGF-ß1-induced lung fibroblast activation in vitro and decreases experimental pulmonary fibrosis in vivo.

Pulmonary fibrosis is an aggressive end­stage disease. Transforming growth factor­ß1 (TGF­ß1) mediates lung fibroblast activation and is essential for the progress of pulmonary fibrosis. BML­111, a lipoxinA4 (LXA4) receptor (ALX) agonist, has been reported to possess anti­ï¬brotic properties. The present study aimed to elucidate whether BML­111 inhibits TGF­ß1­induced mouse embryo lung fibroblast (NIH3T3 cell line) activation in vitro and bleomycin (BLM)­induced pulmonary fibrosis in vivo. In vitro experiments demonstrated that BML­111 treatment inhibits TGF­ß1­induced NIH3T3 cell viability and the expression of smooth muscle α actin (α­SMA), fibronectin and total collagen. Furthermore, this suppressive effect was associated with mothers against decapentaplegic homolog (Smad)2/3, extracellular signal­regulated kinase (ERK) and Akt phosphorylation interference. In vivo experiments revealed that BML­111 treatment markedly improved survival rate and ameliorated the destruction of lung tissue structure. It also reduced interleukin­1ß (IL­1ß), tumor necrosis factor­α (TNF­α) and TGF­ß1 expression in the BLM intratracheal mouse model. In addition, the expression ofα­SMA and extracellular matrix (ECM) deposition (total collagen, hydroxyproline and fibronectin) were also suppressed following BML­111 treatment. However, BOC­2, an antagonist of ALX, partially weakened the effects of BML­111. In conclusion, these results indicated that BML­111 inhibits TGF­ß1­induced fibroblasts activation and alleviates BLM­induced pulmonary fibrosis. Therefore, BML­111 may be used as a potential therapeutic agent for pulmonary fibrosis treatment.

MARESIN 1 PREVENTS LIPOPOLYSACCHARIDE-INDUCED NEUTROPHIL SURVIVAL AND ACCELERATES RESOLUTION OF ACUTE LUNG INJURY.

Acute lung injury (ALI) is characterized by lung inflammation and diffuse infiltration of neutrophils. Neutrophil apoptosis is recognized as an important control point in the resolution of inflammation. Maresin 1 (MaR1) is a new docosahexaenoic acid-derived proresolving agent that promotes the resolution of inflammation. However, its function in neutrophil apoptosis is unknown. In this study, isolated human neutrophils were incubated with MaR1, the pan-caspase inhibitor z-VAD-fmk, and lipopolysaccharide (LPS) to determine the mechanism of neutrophil apoptosis. Acute lung injury was induced by intratracheal instillation of LPS. In addition, mice were treated with MaR1 intravenously at the peak of inflammation and administered z-VAD-fmk intraperitoneally. We found that culture of isolated human neutrophils with LPS dramatically delayed neutrophil apoptosis through the phosphorylation of AKT, ERK, and p38 to upregulate the expression of the antiapoptotic proteins Mcl-1 and Bcl-2, which was blocked by pretreatment with MaR1 in vitro. In mice, MaR1 accelerated the resolution of inflammation in LPS-induced ALI through attenuation of neutrophil accumulation, pathohistological changes, and pulmonary edema. Maresin 1 promoted resolution of inflammation by accelerating caspase-dependent neutrophil apoptosis. Moreover, MaR1 also reduced the LPS-induced production of proinflammatory cytokines and upregulated the production of the anti-inflammatory cytokine interleukin-10. In contrast, treatment with z-VAD-fmk inhibited the proapoptotic action of MaR1 and attenuated the protective effects of MaR1 in LPS-induced ALI. Taken together, MaR1 promotes the resolution of LPS-induced ALI by overcoming LPS-mediated suppression of neutrophil apoptosis.

BML-111 attenuates hemorrhagic shock-induced acute lung injury through inhibiting activation of mitogen-activated protein kinase pathway in rats.

BACKGROUND: Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. Mitogen-activated protein kinase (MAPK) acts as a sensor of tissue injury in models of ischemia-reperfusion injury. Lipoxins are endogenous lipid mediators with potent anti-inflammatory and pro-resolving actions. We hypothesized that BML-111 (a lipoxin A4-receptor agonist) attenuates hemorrhagic shock-induced acute lung injury (ALI) through inhibiting activation of the MAPK pathway. METHODS: We randomized Sprague-Dawley rats into four groups: sham, hemorrhagic shock-resuscitation (HS), HS plus BML-111 (BML-111), and HS plus BML-111 and BOC-2 (BOC-2). Two hours after resuscitation, we collected samples of lung. We obtained bronchoalveolar lavage fluid for neutrophil count. We performed optical microscopy to examine pathologic changes in lungs. Wet/dry ratios, myeloperoxidase expression, interleukin (IL)-1ß and IL-6 levels in lung were measured. We evaluated MAPK activation and the DNA binding activity of activator protein-1 in lung. RESULTS: Treatment with BML-111 reduced the lung damage and wet/dry ratio, neutrophil count in bronchoalveolar lavage fluid, expression of myeloperoxidase, and production of IL-1ß and IL-6 in lung. Phosphorylation of MAPK was also decreased by BML-111 in lung. Furthermore, the DNA binding activity of activator protein-1 was blocked by BML-111. An antagonist of the lipoxin A4-receptor, BOC-2, reversed the protective effect of BML-111 on ALI induced by hemorrhagic shock. CONCLUSIONS: This study indicates that BML-111 attenuated hemorrhagic shock-induced ALI via the MAPK/activator protein-1 signaling pathway. Therefore, BML-111 may have therapeutic potential for hemorrhagic shock-induced ALI.