These results suggest that initial evaluation of serum KL-6 level can predict survival in patients with IPF.

ObjectivesTo examine whether the extent of fibroproliferative changes on high-resolution CT (HRCT) scan influences prognosis, ventilator dependency and the associated outcomes in patients with early acute respiratory distress syndrome (ARDS).DesignA prospective observational cohort study.SettingIntensive care unit in a teaching hospital.Participants85 patients with ARDS who met American-European Consensus Conference Criteria and eligible criteria.InterventionsHRCT scans were performed and prospectively evaluated by two independent observers on the day of diagnosis and graded into six findings according to the extent of fibroproliferation. An overall HRCT score was obtained by previously published method.Primary and secondary outcomesThe primary outcome was 60-day mortality. Secondary outcomes included the number of ventilator-free days, organ failure-free days, the incidence of barotraumas and the occurrence of ventilator-associated pneumonia.ResultsHigher HRCT scores were associated with statistically significant decreases in organ failure-free days as well as ventilator-free days. Multivariate Cox proportional hazards model showed that the HRCT score remained an independent risk factor for mortality (HR 1.20; 95% CI 1.06 to 1.36; p=0.005). Multivariate analysis also revealed that the CT score had predictive value for ventilator weaning within 28 days (OR 0.63; 95% CI 0.48 to 0.82; p=0.0006) as well as for an incidence of barotraumas (OR 1.61; 95% CI 1.08 to 2.38; p=0.018) and for an occurrence of ventilator-associated pneumonia (OR 1.46; 95% CI 1.13 to 1.89; p=0.004). A HRCT score <210 enabled prediction of 60-day survival with 71% sensitivity and 72% specificity and of ventilator-weaning within 28 days with 75% sensitivity and 76% specificity.ConclusionsPulmonary fibroproliferation assessed by HRCT in patients with early ARDS predicts increased mortality with an increased susceptibility to multiple organ failure, including ventilator dependency and its associated outcomes.

Dendritic cells (DCs) play critical roles in innate immunity and adaptive immunity (4). Immature DCs reside in peripheral tissues, where they serve as sentinels for foreign antigens and microbial pathogens. Upon activation, immature DCs undergo maturation and migrate to the lymph nodes. During maturation, DCs acquire an enhanced capacity to form and accumulate peptides, major histocompatibility complex (MHC) class II molecules, costimulatory molecules (such as CD40, CD80, and CD86), and antigens of unknown functions (such as CD83 and DC-LAMP) (10). Mature DCs can prime naïve T cells and initiate primary T-cell-mediated immune responses (4). In addition, there is increasing evidence that DCs in situ induce antigen-specific unresponsiveness or tolerance in central lymphoid organs and in peripheral tissues (4, 31). Thus, DCs play a crucial role during the initiation and regulation of immune responses. Recently, we and others reported that DCs are essential for granuloma formation against bacterial antigens in animal models (12,33,36).Osteopontin (OPN), also known as early T-lymphocyte activation-1 (Eta-1), is a phosphoprotein that contains arginineglycine-aspartate (RGD). Although OPN is classified as an extracellular matrix (ECM) protein, OPN has only recently been shown to be an important component of early cellular immune responses (18). OPN has various functions in chemotaxis for immune cells, tumor metastasis, neovascularization, and host defense, including control of nitric oxide production, control of infection, and control of cell adhesion (3,5,9,21,25). These mechanisms are regulated by posttranslational modifications, such as cleavage by thrombin, addition of a glucose chain, and phosphorylation. Various immunological disorders are associated with high levels of OPN expression (8,15). Analyses of OPN-deficient mice revealed that OPN plays an important immunological role in granuloma formation (23), acid-fast bacillus disease (21), and carcinoma metastasis (5). The role of OPN in inflammation suggests that ECM-related proteins may function as pleiotropic cytokines to regulate immune responses. Activated macrophages, lymphocytes, and natural killer (NK) cells produce OPN in response to various stimuli (23). However, there are no reports of the effects of OPN on DCs, with the exception of a single report of the migratory effect of OPN on cutaneous Langerhans cells and DCs in a mouse allergic cutaneous hypersensitivity model (34). The direct effect of OPN on the development and activation of DCs has not been clarified. Thus, we sought to characterize the functional interaction between OPN and DCs by examining the effects of OPN on differentiation, maturation, and function of human monocyte-derived immature and mature DCs. We report here that human monocyte-derived dendritic cell (Mo-DC) can produce OPN that enhances differentiation, maturation, and survival of DCs by autocrine and/or paracrine pathways. MATERIALS AND METHODSReagents. Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) ...

It has previously been reported that the expression of monocyte chemoattractant protein-1 (MCP-1) in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF) was different from that in the tissues of patients with other interstitial lung diseases (ILDs). The aim of this study was to determine whether this difference reflects the amount of MCP-1 in the bronchoalveolar lavage fluid (BALF) or serum of patients with ILD, and whether such a correlation, if it exists, is clinically useful. MCP-1 concentrations in the BALF and sera were evaluated in 86 patients with ILDs including IPF, acute interstitial pneumonia, interstitial pneumonia with collagen vascular disease (IP-CVD), chronic interstitial pneumonia (CIP), bronchiolitis obliterans-organizing pneumonia, sarcoidosis, hypersensitivity pneumonitis, and in 10 normal healthy volunteers who were controls (NC). BALF MCP-1 levels were significantly elevated in the IPF, IP-CVD, CIP and sarcoidosis groups compared with the NC group. The level in the IPF group was significantly higher than that in any other patient group. Serum MCP-1 levels in the IPF, IP-CVD, CIP and sarcoidosis groups were significantly higher than the NC group. No statistical difference was found in serum MCP-1 levels between the IPF, IP-CVD and CIP groups. BALF MCP-1 levels were significantly higher than serum MCP-1 levels in the IPF group and lower than in the IP-CVD and CIP groups. Serum MCP-1 levels correlated with the clinical course of ILD treated with corticosteroid therapy. These results show that measurement of monocyte chemoattractant protein-1 levels in both bronchoalveolar lavage fluid and serum may be helpful in discriminating idiopathic pulmonary fibrosis from other types of interstitial lung disease and that monitoring of serum monocyte chemoattractant protein-1 may be useful for predicting the clinical course of interstitial lung diseases.

When sampling inhaled antigens, dendritic cells (DC) must penetrate the tight junction (TJ) barrier while maintaining the TJ seal. In matrix metalloproteinase (MMP)-9-deficient mice, in vivo experiments suggest that migration of DC into air spaces is impaired. To examine the underlying mechanisms, we established a well-defined in vitro model using mouse tracheal epithelial cells and mouse bone marrow DC (BMDC). Transmigration was elicited with either macrophage inflammatory protein (MIP)-1alpha or MIP-3beta in a time-dependent manner. Control MMP-9(+/+) BMDC cultured with granulocyte macrophage-colony-stimulating factor for 7 d showed a 30-fold greater transepithelial migration toward MIP-3beta than MIP-1alpha, indicating a more mature DC phenotype. MMP-9(-/-) BMDC as well as MMP-9(+/+) BMDC in the presence of the MMP inhibitor GM6001, although showing a similar preference for MIP-3beta, were markedly impaired in their ability to traverse the epithelium. Expression levels of CCR5 and CCR7, however, were similar in both MMP-9(-/-) and MMP-9(+/+) BMDC. Expression of the integral TJ proteins, occludin and claudin-1, were examined in BMDC before and after transepithelial migration. Interestingly, occludin but not claudin-1 was degraded following transepithelial migration in both MMP-9(-/-) and control BMDC. In addition, there was a > 2-fold increase in claudin-1 expression in MMP-9(-/-) as compared with control BMDC. These observations indicate that occludin and claudin-1 are differentially regulated and suggest that the lack of MMP-9 may affect claudin-1 turnover.