Ken-Ichiro Inoue

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with inflammatory disorders such as pancreatitis, shock and disseminated intravascular coagulation (DIC). Previous in vitro studies have demonstrated that serine protease inhibitors may have anti-inflammatory properties at sites of inflammation. However, the therapeutic effects of UTI in vivo remain unclarified, as commercial UTI has been developed to act against humans, with the activity and selectivity toward the relevant animal UTI being less characterized. In this review, we introduce the roles of UTI in experimental endotoxin (lipopolysaccharide; LPS)-related inflammatory disorders using UTI-deficient (-/-) and corresponding wild-type mice. Our experiments using genetic approach suggest that endogenous UTI can protect against the systemic inflammatory response and subsequent organ injury induced by LPS, at least partly, through the inhibition of pro-inflammatory cytokine and chemokine expression, which provide important in vivo evidence and understanding about a protective role of UTI in inflammatory conditions. Using genetically targeted mice selectively lacking UTI, UTI has been evidenced to provide an attractive 'rescue' therapeutic option for endotoxin-related inflammatory disorders such as DIC, acute lung injury and acute liver injury.

We read with great interest a recent in vivo study by Nemmar et al. (2010) and would like to add some comments to the paper regarding the systemic effects of pulmonary exposure to diesel exhaust particles (DEP). In their interesting study, Nemmar et al. showed that intratracheal administration of DEP exacerbates acute renal failure induced by cisplatin (CP) and accompanying respiratory distress, suggesting that DEP is risky for patients with devastating renal impairment. Of note, airway pathophysiology accompanied by renal failure is worsened by DEP exposure. Although mechanically undefined, it seems that marked pulmonary congestion is widespread only in the CP + DEP group (Fig. 9). We have previously observed similar results, in which marked pulmonary edema in pathological condition was shown in combination with DEP or concentrated ambient particulate matter (PM) (Inoue et al., 2006a; Inoue et al., 2006b; Takano et al., 2002; Yanagisawa et al., 2003). Collectively, our work and the studies of Nemmar et al. indicate that inhaled DEP (and PM) may adversely affect pulmonary edema independent of the main site of damage (since Nemmar et al. report renal toxicity). It can be speculated that DEP directly/indirectly disrupts the epithelial/endothelial barrier to allow water and several proteins with inflammatory leukocytes enter into the airspace as we confirmed by lung water content and bronchoalveolar lavage fluid protein concentration in our previous report (Inoue et al., 2006a). Thus, above-mentioned parameters might provide further information regarding pulmonary edema to the study by Nemmar et al. Nonetheless, the mechanisms in which DEP induce/enhance pulmonary edema remain to be clarified in the future.

Japan's largest platform for academic e-journals: J-STAGE is a full text database for reviewed academic papers published by Japanese societies

Although fungi have been implicated as initiating/deteriorating factors for allergic asthma, their contributing components have not been fully elucidated. We previously isolated soluble β-glucan from Candida albicans (CSBG) (Ohno et al., 2007). In the present study, the effects of CSBG exposure on airway immunopathology in the presence or absence of other immunogenic allergen was investigated in vivo, and their cellular mechanisms were analyzed both in vivo and in vitro. In vivo, ICR mice were divided into 4 experimental groups: vehicle, CSBG (25 μg/animal), ovalbumin (OVA: 2 μg/animal), and CSBG + OVA were repeatedly administered intratracheally. The bronchoalveolar lavage cellular profile, lung histology, levels of cytokines and chemokines in the lung homogenates, the expression pattern of antigen-presenting cell (APC)-related molecules in the lung digests, and serum immunoglobulin values were studied. In vitro, the impacts of CSBG (0–12.5 μg/ml) on the phenotype and function of immune cells such as splenocytes and bone marrow-derived dendritic cells (BMDCs) were evaluated in terms of cell proliferation, the surface expression of APC-related molecules, and OVA-mediated T-cell proliferating activity. In vivo, repeated pulmonary exposure to CSBG induced neutrophilic airway inflammation in the absence of OVA, and markedly exacerbated OVA-related eosinophilic airway inflammation with mucus metaplasia in mice, which was concomitant with the amplified lung expression of Th2 cytokines and IL-17A and chemokines related to allergic response. Exposure to CSBG plus OVA increased the number of cells bearing MHC class II with or without CD80 in the lung compared to that of others. In vitro, CSBG significantly augmented splenocyte proliferation in the presence or absence of OVA. Further, CSBG increased the expression of APC-related molecules such as CD80, CD86, and DEC205 on BMDCs and amplified OVA-mediated T-cell proliferation through BMDCs. CSBG potentiates allergic airway inflammation with maladaptive Th immunity, and this potentiation was associated with the enhanced activation of APCs including DC.