Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary infection. Alveolar macrophages (AM) are at the center of the pathogenesis of the development of ALI. Interleukin-1β (IL-1β) is one of the key pro-inflammatory mediators and its maturation is tightly controlled by the formation and activation of the inflammasome. The biological effects of IL-1β are mediated through IL-1 receptor (IL-1R). In this study, we investigated the influence of LPS-induced IL-1β release and IL-1RI upregulation on the development of lung inflammation. We demonstrated that in AM, LPS-TLR4 signaling not only activates Nlrp3 inflammasome activation and subsequent release of IL-1β, but also up-regulates IL-1RI expression on AM surface through MyD88 and NF-κB dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1β and results in pyroptosome formation, which in turn leads to AM pyroptosis, a type of caspase-1-dependent inflammatory cell death. We further showed that AM pyroptosis exaggerates lung inflammation. The present study demonstrates a novel mechanism underlying LPS-induced innate immunity; that is, a secondary upregulation of IL-1β-IL-1RI signaling is responsible for AM pyroptosis and augmented lung injury in response to LPS.

BACKGROUND.: Postoperative interferon‐α (IFN‐α) therapy improved survival in patients with hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC). The identification of predictive markers of outcome will help to select patients who are most likely to benefit from treatment.METHODS.: An immunohistochemical study of P48 was performed on specimens that were collected from patients in a randomized trial who received postoperative IFN‐α therapy (Group 1; n = 80 patients) and who did not receive postoperative IFN‐α therapy (Group 2; n = 75 patients). Positive P48 expression was graded as ≥20% positive cells in 1 sample.RESULTS.: Eighty‐one patients were positive for P48, and 74 patients were negative for P48. The clinicopathologic data were comparable between patients with P48‐negative and P48‐positive staining. Disease‐free survival (DFS) and overall survival (OS) in P48‐positive patients were better than that in P48‐negative patients in Group 1 (DFS, P = .036; OS, P = .014), however, DFS and OS did not differ between patients with positive and negative P48 in Group 2. OS in P48‐positive patients from Group 1 was better than that in patients with P48‐positive patients from Group 2 (OS, P = .001) but did not differ when P48 was negative. In Group 1, the risk factors for DFS were cirrhosis and P48 staining, and the risk factors for OS were tumor differentiation and P48 staining. Receiver operating curve analysis indicated that, in the first 2 years of DFS, combined cirrhosis and P48 had good predictive accuracy; and, in the first 4 years of OS, combined tumor differentiation and P48 had good predictive accuracy.CONCLUSIONS.: P48 was useful as a predictive marker of outcome after postoperative IFN‐α treatment in patients with HBV‐related HCC. Cancer 2006. © 2006 American Cancer Society.

Severe and acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with a high mortality. Since COPD is an airway inflammatory disease, and heparin has shown anti-inflammatory effects in previous studies, we evaluated the clinical effect of low molecular weight heparin (LMWH; nadroparin) in COPD patients admitted into the hospital due to acute exacerbations. Sixty-six patients admitted to the intensive care unit (ICU) were randomly divided into control group (n = 33) and LMWH group (n = 33). The control group received conventional treatment, including oxygen therapy (non-invasive or conventional mechanical ventilation), anti-infection, atomization expectorant, spasmolysis, anti-asthmatics, and nutritional support. The LMWH group received the same treatment plus LMWH for 1 week. The levels of plasma C-reactive protein, interleukin-6, and fibrinogen were measured. The main outcomes were duration of mechanical ventilation, length of ICU stay, and hospital stay. There were no significant differences between the groups with respect to demographics, severity of illness, and gas exchange variables. The levels of plasma C-reactive protein, interleukin-6, and fibrinogen were significantly decreased in the LMWH group. LMWH significantly reduced the mean duration of mechanical ventilation (6.6 days vs. 3.8 days; p < 0.01), the length of ICU stay (8.5 days vs. 5.6 days; p < 0.01) and hospital stay (14.3 days vs. 11.3 days; p < 0.01). The addition of LMWH to standard therapy benefits COPD patients with acute exacerbation.

Background: Ceftazidime-avibactam (CZA) has been approved in vitro activity against carbapenem-resistant K. pneumoniae (CRKP), but the experience for the treatment of CRKP in liver transplantation (LT) recipients was limited, and previous data on its efficacy in this setting are lacking. Methods: LT recipients with CRKP infection who received CZA treatment were reviewed retrospectively, microbiological and clinical response, adverse events were also assessed. The primary outcome was 30-day mortality after CZA administration. Results: CZA was used in 21 LT recipients (including 4 pediatric patients) with CRKP infections after failure with other antimicrobials. CZA was administered as monotherapy in 4 patients. Median time from the onset of CRKP infection until the initiation of CZA treatment was 2 days (IQR, 1– 6.5), and the median treatment duration was 12 days (IQR, 8.5– 18.5). The mortality at 14 days, 30 days and all-cause was 28.6%, 38.1% and 42.9%, respectively. In adult patients, clinical response of 14 days and 30 days was 70.6% (12/17) and 58.8% (10/17), respectively, while in pediatric patients the 14-day and 30-day clinical response were both 75%, respectively. The relapse rate during the treatment developed in 3 patients after 30 days with the cessation of CZA monotherapy. CZA resistance was not detected in any case and 3 (3/21, 14.3%) patients developed acute kidney injury related to uncontrolled infection. Conclusion: CZA shows promising results, even in monotherapy, for the treatment of patients with severe infections due to carbapenem-resistant K. pneumoniae among LT recipients. The emergence of resistance to CZA was not observed.