The mechanism underlying the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) is suppression of the activity of cyclooxygenase (COX). It has been surmised that selective COX-2 inhibitors can inhibit only the production of prostaglandin (PG) related to inflammation but not PG related to physiological functions. However, COX-2 is present in some tissues with physiological function. It has been established that selective COX-2 inhibitors are safer with respect to upper gastrointestinal tract complications than traditional nonselective NSAIDs. Furthermore, selective COX-2 inhibitors are effective in suppressing familial adenomatous polyposis. In contrast, recent studies have shown that selective COX-2 inhibitors and non-selective NSAIDs increase the cardiovascular risk. In Japan, celecoxib, a selective COX-2 inhibitor, was approved for clinical use in 2007. In this review, we outline the benefits and advantages of selective COX-2 inhibitors and suggest how best to use NSAIDs in daily clinical practice.

抄録全体を表示

Dry eye is a multifactorial disease of the tears and the ocular surface that results in symptoms of discomfort,visual disturbance, and tear film instability with potential damage to the ocular surface. Increased osmolarityof the tear film and inflammation in the lacrimal system and ocular surface are important operational factors inthe genesis of some dry eye disorders. Mechanical abrasion secondary to tear deficiency may create aninflammatory environment where conjunctival epithelial cells and lymphocytes are stimulated to produce andsecrete various cytokines into the tear film. Elevated cytokine levels within the tear film, combined with reducedconcentrations of essential lacrimal-gland derived factors such as epidermal growth factor (EGF) andretinol create an environment in which terminal differentiation of the ocular surface epithelium is impaired.The histopathologic changes in the minor salivary gland and lacrimal gland biopsy are characterized by focaland/or diffuse lymphoid cell infiltrates and parenchymal destruction. The majority of cells in glandular biopsyspecimens are CD4+ cells with a small proportion of CD8+T-cells.
Apoptosis of acinar cells and inflammatory cells are also key events in relation to development of dry eyes.We previously showed the presence of apoptosis of acinar cells, FasL expression in lacrimal glands and thatthe FasL expression highly correlated with glandular function especially in those patients without glandularenlargement. FasL expression of infiltrating lymphocytes were low in the lacrimal glands of patients with SSwith enlarged exocrine glands where the lacrimal gland function was well preserved even with massive lymphocyteinvasion. In other words, the infiltration of lymphocytes alone did not cause glandular dysfunction.Apoptosis of acinar cells may explain these differences. Oxidative stress is recently receiving the attention ofresearchers and clinicians as a possible mechanism in the development of dry eye disease. Tsubota et alhave shown, for the first time in the literature, increases in oxidative stress markers, changes in antioxidantrelatedgene expression, and discordance in differentiation capacity in corneal epithelia in dry eye conditions,suggesting a strong relationship between the accumulation of oxidative stress and the etiology of cornealepithelial alterations in blink-suppressed dry eye. The management of oxidative stress may provide a newapproach for the prevention and therapeutic treatment for dry eye syndromes. The increased awareness ofoxidative stress related to disease and the need to measure the delicate balance that exists between freeradicals and the systems in place to regulate them has given rise to a demand for new research tools.

抄録全体を表示

Cysteinyl leukotrienes (CysLTs: leukotrienes C₄, D₄, and E₄) have long been implicated in the pathogenesis of allergic diseases such as asthma. CysLTs are potent bronchoconstrictors that have the additional effects of edema, mucous secretion, and eosinophilic accumulation, and airway remodeling. LTE₄ has been identified as a major metabolite of LTC₄, and urinary LTE₄ (U-LTE₄) is considered as the most reliable analytic parameter for monitoring the endogenous synthesis of CysLTs. From our extensive study of U-LTE₄ in adult asthma, we identified four factors for hyperleukotrienuria. These factors were aspirin-intolerance, eosinophilic nasal polyposis (ENP), vasculitis, and severe asthma. In ENP there is prominent infiltration of eosinophils in the sinus and polyp tissues, which is linked to adult asthma and aspirin-sensitivity, and ENP is the most important factor for overproduction of CysLTs in asthmatics. We demonstrated that there is a significant decrease in the U-LTE₄ concentration after the sinus surgery of asthmatics with and without aspirin intolerance. Recent studies reported that ENP tissue contain and produce a large amount of CysLTs, and there is a close relationship between CysLT production and eosinophil accumulation in ENP. These observations suggest that ENP is not only a local allergic disease, but also a systemic inflammatory disease with CysLT overproduction.

抄録全体を表示

In the field of head and neck surgery, tracheal resection is frequently required for patients with cancer or trauma. There are several approaches for reconstructing the tracheal wall, but almost all require repeated skilled surgeries, which intend to fill the defect and create new airway space using autologous or artificial grafts.
Regenerative medicine has made remarkable progress and has been applied clinically in some organs. Thus in this study, the usefulness of a tissue engineering approach for tracheal reconstruction was evaluated. A partial defect was created in canine cervical tracheas. A scaffold made of polypropylene and collagen sponge was sutured at the defect site. Postoperative status was evaluated by endoscopy, radiography, and histology. In all five cases, epithelialization of the scaffold luminal surface was observed without deformity or complications. Histological data also supported the functional regeneration of the trachea using this approach. This simple tissue engineering approach is a good method for reconstruction of the trachea with partial defects.

抄録全体を表示

RNA splicing has two different processes: namely, constitutive and alternative splicing. The latter has now emerged as an important mechanism which produces a high degree of protein diversity at a low genetic cost. Importantly, alternative splicing generates functionally distinct products from the same apoptosisrelated genes including Bcl-x, caspase-9, caspase-2, Fas and caspase-8. Furthermore, many genes in the immune system are alternatively spliced including CD45, CD44, CTLA-4 and ICAM-1, thus indicating that alternative splicing plays a critical role in both T-cell homeostasis and the activation-induced cell death (AICD). A critical issue in alternative splicing regulation is the specific recognition of the splice site, which mainly depends on the phosphorylation level of serine/arginine splicing factors (SR proteins). SR proteins are all subjected to phosphorylation and dephosphorylation on Ser residues within their RS domains. Their activities are tightly regulated by reversible phosphorylation. Recently, intensive efforts have been made to obtain new insight into how intracellular signaling regulates RNA splicing. This brief summary outlines both the mechanism and the role of alternative splicing through the intracellular signaling pathways.

抄録全体を表示

The development of vitally functional biliary substitutes has long been awaited. However, despite numerous approaches for replacement of biliary defects with a variety of materials, an "artificial bile duct" has not yet been realized clinically. Recently, tissue engineering has become a promising technique for regenerating defective organs. In the present study, we attempted to regenerate bile duct tissue using in situ tissue engineering. We prepared experimental scaffolds composed of collagen sponge (CS) as a base material and performed biliary reconstruction using these artificial bile ducts in canine models. We replaced circumferential biliary defects with our prosthesis in 7 dogs. In group A, we used prostheses consisting entirely of CS with biliary stenting for 2 weeks (2 dogs). In group B, the biliary stents were left in place for 12 weeks (2 dogs). In group C, we used prostheses consisting of a CS reinforced with a polypropylene (PP) mesh framework with biliary stenting for 2 weeks (3 dogs). In group A, stenosis of the prostheses progressed and the dogs became jaundiced within 2 months. In group B, regeneration of biliary epithelium was not seen, although the prostheses maintained the patency of the duct due to long-term stenting. In group C, a reconstructed bile duct composed of newly formed biliary epithelium and connective tissue successfully replaced the defects and maintained the patency without long-term stenting. Thus, our artificial bile duct consisting of CS and a PP mesh framework shows potential for regeneration of bile duct tissue.

抄録全体を表示