Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma.

BACKGROUND: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners-e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induced airway responses is not well defined. The goal of this study is to elucidate the role of RXRs in asthma pathogenesis and the potency of RXR partial agonist in the treatment of allergic airway inflammation and airway hyperresponsiveness using a murine model of asthma. METHODS: We investigated the effect of a novel RXR partial agonist (NEt-4IB) on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in a murine model of asthma. Balb/c mice were sensitized (days 0 and 14) and challenged (days 28-30) with ovalbumin (OVA), and airway inflammation and airway responses were monitored 48 h after the last OVA challenge. NEt-4IB was administered orally on days 25 to 32. RESULTS: Oral administration of NEt-4IB significantly suppressed AHR and inflammatory cell accumulation in the airways and attenuated the levels of TNF-α in the lung and IL-5, IL-13 and NO levels in bronchoalveolar lavage (BAL) fluid and the number of periodic acid Schiff (PAS)-positive goblet cells in lung tissue. Treatment with NEt-4IB also significantly suppressed NF-κB expression. CONCLUSION: These data suggest that RXRs may be of crucial importance in the mechanism of allergic asthma and that the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of allergic airway inflammation and airway hyperresponsiveness in a model of allergic asthma.

IL-23 Is Essential for the Development of Elastase-Induced Pulmonary Inflammation and Emphysema.

We recently reported that IL-17A plays a critical role in the development of porcine pancreatic elastase (PPE)-induced emphysema. The proliferation of T-helper type 17 (Th17) cells was induced by IL-23. To determine the contribution of IL-23 to the development of pulmonary emphysema, a mouse model of PPE-induced emphysema was used in which responses of IL-23p19-deficient (IL-23-/-) and wild-type (WT) mice were compared. Intratracheal instillation of PPE induced emphysematous changes in the lungs and was associated with increased levels of IL-23 in lung homogenates. Compared with WT mice, IL-23-/- mice developed significantly lower static compliance values and markedly reduced emphysematous changes on histological analyses after PPE instillation. These changes were associated with lower levels of IL-17A and fewer Th17 cells in the lung. The neutrophilia seen in bronchoalveolar lavage fluid of WT mice was attenuated in IL-23-/- mice, and the reduction was associated with decreased levels of keratinocyte-derived cytokine and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid. Treatment with anti-IL-23p40 monoclonal antibody significantly attenuated PPE-induced emphysematous changes in the lungs of WT mice. These data identify the important contributions of IL-23 to the development of elastase-induced pulmonary inflammation and emphysema, mediated through an IL-23/IL-17 pathway. Targeting IL-23 in emphysema is a potential therapeutic strategy for delaying disease progression.

Increased Serum KL-6 Levels Induced by Pulmonary Mycobacterium Avium Complex Infection in a Patient with RA-associated Lung Disease.

KL-6 is a glycoprotein found predominantly on type II pneumocytes and alveolar macrophages, and often shows increased serum levels in patients with interstitial pneumonia. We report a case of mycobacterium avium complex (MAC) infection whose disease activity was correlated with KL-6 levels in serum. During treatment of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) with prednisolone, chest image findings improved in association with decreased KL-6 levels. Following tapering of prednisolone, chest image findings deteriorated again as levels of KL-6 increased, suggesting recurrence of RA-ILD. Bronchoscopic examination revealed active MAC infection. Treatment of MAC infection not only improved chest image findings but also decreased KL-6 levels in serum, suggesting that KL-6 was increased by active MAC infection by itself, not by recurrence of RA-ILD. To the best of our knowledge, this is the first documentation of KL-6 elevation in serum in association with active MAC infection.

Emphysema requires the receptor for advanced glycation end-products triggering on structural cells.

Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The receptor for advanced glycation end-products (RAGE) is a multiligand cell surface receptor reported to be involved in the process of acute alveolar epithelial cell injury. However, studies that address the role of RAGE in pulmonary emphysema are inconclusive. We investigated the role of RAGE in the development of elastase-induced pulmonary inflammation and emphysema in mice. RAGE-sufficient (RAGE(+/+)) mice and RAGE-deficient (RAGE(-/-)) mice were treated with intratracheal elastase on Day 0. Airway inflammation, static lung compliance, lung histology, and the levels of neutrophil-related chemokine and proinflammatory cytokines in bronchoalveolar lavage fluid were determined on Days 4 and 21. Neutrophilia in bronchoalveolar lavage fluid, seen in elastase-treated RAGE(+/+) mice, was reduced in elastase-treated RAGE(-/-) mice on Day 4, and was associated with decreased levels of keratinocyte chemoattractant, macrophage inflammatory protein-2, and IL-1ß. Static lung compliance values and emphysematous changes in the lung tissue were decreased in RAGE(-/-) mice compared with RAGE(+/+) mice on Day 21 after elastase treatment. Experiments using irradiated, bone marrow-chimeric mice showed that the mice expressing RAGE on radioresistant structural cells, but not hematopoietic cells, developed elastase-induced neutrophilia and emphysematous change in the lung. In contrast, mice expressing RAGE on hematopoietic cells, but not radioresistant structural cells, showed reduced neutrophilia and emphysematous change in the lung. These data identify the importance of RAGE expressed on lung structural cells in the development of elastase-induced pulmonary inflammation and emphysema. Thus, RAGE represents a novel therapeutic target for preventing pulmonary emphysema.

Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness.

The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE-/-) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE-/- mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE+/+ mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE-/- mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses.

Complication of chronic eosinophilic pneumonia in an elderly patient with Sjögren syndrome.

An 81-year-old Japanese male with primary Sjögren syndrome (pSS) developed a low-grade fever and productive cough which were refractory to antibiotic therapy. Based on the high level of eosinophils observed in his bronchial alveolar lavage, he was diagnosed with chronic eosinophilic pneumonia (CEP) and successfully treated by oral prednisolone. Interstitial lung diseases associated with pSS (pSS-ILDs) usually present as nonspecific interstitial pneumonia or usual interstitial pneumonia; therefore, the present case is extremely unique in that the patient's condition was complicated with CEP. A diagnosis of advanced gallbladder cancer was made in the patient's clinical course, suggesting the advisability of a whole-body workup in cases of pSS, especially in elderly patients.

Effect of a cysteinyl leukotriene receptor antagonist on experimental emphysema and asthma combined with emphysema.

The incidence of overlapping bronchial asthma and chronic obstructive pulmonary disease has increased in recent years. Cysteinyl leukotrienes (CysLTs) play an important role in asthma, and the type 1 CysLT receptor (CysLT1R) is expressed by many inflammatory cells. We evaluated the effect of montelukast, a CysLT1R antagonist, on mouse models of asthma, porcine pancreatic elastase (PPE)-induced emphysema, and asthma combined with emphysema. Mice were sensitized with ovalbumin (OVA) on Days 0 and 14 and subsequently challenged with OVA on Days 28, 29, and 30. Pulmonary emphysema was induced by intratracheal instillation of PPE on Day 25. Mice were treated subcutaneously with montelukast or vehicle from Day 25 to Day 31. Airway hyperresponsiveness (AHR), static compliance; the number of inflammatory cells, the levels of cytokines, chemokines, LTs, and perforin in the bronchoalveolar lavage fluid, and the quantitative morphometry of lung sections were analyzed on Day 32. Treatment with montelukast significantly attenuated the AHR and eosinophilic airway inflammation in OVA-sensitized and OVA-challenged mice. Administration of montelukast significantly reduced the AHR, static compliance, and neutrophilic airway inflammation, while attenuating emphysematous lung changes, in PPE-treated mice. In PPE-treated mice subjected to allergen sensitization and challenges, montelukast significantly suppressed the AHR, static compliance, and eosinophilic and neutrophilic airway inflammation in addition to the development of experimentally induced emphysema in the lungs. Our data suggest that CysLT1R antagonists may be effective in ameliorating the consequences of PPE-induced lung damage and the changes that follow allergen sensitization and challenges.

Aortic vascular graft infection caused by Cardiobacterium valvarum: a case report.

A 53-year-old man with a past medical history of total arch replacement surgery and severe aortic regurgitation presented with a 1-month history of persistent general malaise, anorexia, body weight loss and night sweats. His recent history included gingival hyperplasia for 6 years, gingivitis after tooth extraction 3 years before, prolonged inflammatory status for 4 months, fundal hemorrhage and leg tenderness for 2 months. A pathogen was detected from blood culture, but conventional microbiological examination failed to identify the pathogen. The organism was eventually identified as Cardiobacterium valvarum by 16S rRNA analysis, and the patient was diagnosed with infective endocarditis and prosthetic vascular graft infection. The patient received intravenous antibiotic therapy using a combination of ceftriaxone and levofloxacin for 5 weeks and was discharged with a good clinical course. C. valvarum is a rare human pathogen in clinical settings. Only 10 cases have been reported to date worldwide, and therefore, the clinical characteristics of C. valvarum infection are not fully known. This is a first well-described case of C. valvarum infection in Japan, and further, a first report of aortic prosthetic vascular graft infection worldwide. Identification of C. valvarum is usually difficult due to its phenotypic characteristics, and molecular approaches would be required for both clinicians and microbiologists to facilitate more reliable diagnosis and uncover its clinical picture more clearly.

Long-term observation of osteomalacia caused by adefovir-induced Fanconi's syndrome.

A 64-year-old man suffering polyarthralgia and bone pain was referred to our hospital. Renal dysfunction, hypophosphatemia and increased levels of bone alkaline phosphatase were found. The patient's serum creatinine level had gradually increased after the initiation of adefovir dipivoxil administration for hepatitis B. In agreement with multifocal uptakes of bone scintigraphy, iliac bone biopsy revealed an abnormal increase in osteoid tissues. Reducing the dose of adefovir and initiating the administration of eldecalcitol were effective for reducing proteinuria and glucosuria, and for ameliorating bone pain with an increase in serum phosphate level. This case first showed a clinical course of hypophosphatemic osteomalacia caused by secondary Fanconi's syndrome for 8 years after adefovir administration. Early diagnosis is important for the reversibility of bone damage and for a better renal prognosis.

Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses.

BACKGROUND: Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice. METHODS: BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. RESULTS: Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-ß1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. CONCLUSION: These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil- and eosinophil-dominant phases of the response to secondary allergen challenge.

IL-17A is essential to the development of elastase-induced pulmonary inflammation and emphysema in mice.

BACKGROUND: Pulmonary emphysema is characterized by alveolar destruction and persistent inflammation of the airways. Although IL-17A contributes to many chronic inflammatory diseases, it's role in the inflammatory response of elastase-induced emphysema remains unclear. METHODS: In a model of elastase-induced pulmonary emphysema we examined the response of IL-17A-deficient mice, monitoring airway inflammation, static compliance, lung histology and levels of neutrophil-related chemokine and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. RESULTS: Wild-type mice developed emphysematous changes in the lung tissue on day 21 after elastase treatment, whereas emphysematous changes were decreased in IL-17A-deficient mice compared to wild-type mice. Neutrophilia in BAL fluid, seen in elastase-treated wild-type mice, was reduced in elastase-treated IL-17A-deficient mice on day 4, associated with decreased levels of KC, MIP-2 and IL-1 beta. Elastase-treated wild-type mice showed increased IL-17A levels as well as increased numbers of IL-17A+ CD4 T cells in the lung in the initial period following elastase treatment. CONCLUSIONS: These data identify the important contribution of IL-17A in the development of elastase-induced pulmonary inflammation and emphysema. Targeting IL-17A in emphysema may be a potential therapeutic strategy for delaying disease progression.

Requirement for chemokine receptor 5 in the development of allergen-induced airway hyperresponsiveness and inflammation.

Chemokine receptor (CCR) 5 is expressed on dendritic cells, macrophages, CD8 cells, memory CD4 T cells, and stromal cells, and is frequently used as a marker of T helper type 1 cells. Interventions that abrogate CCR5 or interfere with its ligand binding have been shown to alter T helper type 2-induced inflammatory responses. The role of CCR5 on allergic airway responses is not defined. CCR5-deficient (CCR5(-/-)) and wild-type (CCR5(+/+)) mice were sensitized and challenged with ovalbumin (OVA) and allergic airway responses were monitored 48 hours after the last OVA challenge. Cytokine levels in lung cell culture supernatants were also assessed. CCR5(-/-) mice showed significantly lower airway hyperresponsiveness (AHR) and lower numbers of total cells, eosinophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid compared with CCR5(+/+) mice after sensitization and challenge. The levels of IL-4 and IL-13 in BAL fluid of CCR5(-/-) mice were lower than in CCR5(+/+) mice. Decreased numbers of lung T cells were also detected in CCR5(-/-) mice after sensitization and challenge. Transfer of OVA-sensitized T cells from CCR5(+/+), but not transfer of CCR5(-/-) cells, into CCR5(-/-) mice restored AHR and numbers of eosinophils in BAL fluid after OVA challenge. Accordingly, the numbers of airway-infiltrating donor T cells were significantly higher in the recipients of CCR5(+/+) T cells. Taken together, these data suggest that CCR5 plays a pivotal role in allergen-induced AHR and airway inflammation, and that CCR5 expression on T cells is essential to the accumulation of these cells in the airways.

Blocking the leukotriene B4 receptor 1 inhibits late-phase airway responses in established disease.

Most of the studies investigating the effectiveness of blocking the leukotriene B4 (LTB4) receptor 1 (BLT1) have been performed in models of primary or acute allergen challenge. The role of the LTB4-BLT1 pathway in secondary challenge models, where airway hyperresponsiveness (AHR) and airway inflammation have been established, has not been defined. We investigated the effects of blocking BLT1 on early- and late-phase development of AHR and airway inflammation in previously sensitized and challenged mice. Female BALB/c mice were sensitized (Days 1 and 14) and challenged (primary, Days 28-30) with ovalbumin. On Day 72, mice were challenged (secondary) with a single OVA aerosol, and the early and late phases of AHR and inflammation were determined. Specific blockade of BLT1 was attained by oral administration of a BLT1 antagonist on Days 70 through 72. Administration of the antagonist inhibited the secondary ovalbumin challenge-induced alterations in airway responses during the late phase but not during the early phase, as demonstrated by decreases in AHR and in bronchoalveolar lavage neutrophilia and eosinophilia 6 and 48 hours after secondary challenge. The latter was associated with decreased levels of KC protein, macrophage inflammatory protein 2, and IL-17 in the airways. These data identify the importance of the LTB4-BLT1 pathway in the development of late-phase, allergen-induced airway responsiveness after secondary airway challenge in mice with established airway disease.

Churg-Strauss syndrome with necrosis of toe tips.

Churg-Strauss syndrome (CSS) is a granulomatous necrotizing vasculitis of unknown etiology associated with bronchial asthma. Despite affecting small to medium-sized vessels, necrosis of the digits due to vasculitis is extremely rare. We report a case of CSS with necrosis of the toe tips. A 37-year-old woman with asthma, who had been diagnosed with CSS 2 years ago, was admitted to our hospital with an exacerbation of CSS. The patient had a high grade fever and complained of abdominal pain and numbness of the lower extremities. Blood examination revealed marked eosinophilia. The fever pattern, abdominal pain and blood eosinophilia showed improvement by combination treatment with prednisolone and cyclophosphamide. However, the color of her right toe tips changed, and necrosis finally resulted despite antithrombotic therapy. Arteriography showed narrowing of the dorsalis pedis artery and of the more peripheral arteries of her right leg. Stump plasty with negative pressure dressing therapy for the toe tips, but not amputation, was done to preserve the leg function. While numbness of the extremities remained, no recurrence of necrosis was seen. Clinicians need to be aware that rare complications of CSS, including necrosis of the digits, can occur.

Successful extracorporeal life support for life-threatening hypercapnia with bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation.

Bronchiolitis obliterans (BO) is a disease with a poor prognosis, and a key factor that limits long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). We here report a case of a 31-year woman with acute lymphatic leukemia, which was treated by chemotherapy and HSCT, and consequently developed BO 2 years after HSCT. A non-tuberculous mycobacterial infection occurred and showed gradual exacerbation. She started taking anti-mycobacterial drugs, but lost appetite, felt tired and finally lost consciousness one month after beginning medication. Arterial blood gas revealed marked hypercapnia. Using extracorporeal life support (ECLS), the carbon dioxide concentration was reduced and her consciousness recovered. To our knowledge, this is the first case in which ECLS was successfully used for hypercapnia in a patient with BO.

Hypersensitivity Pneumonitis Caused by a Home Ultrasonic Humidifier Contaminated with Candida guilliermondii.

We herein report the first documented case of acute hypersensitivity pneumonitis in which Candida guilliermondii was the possible causative organism. A young Japanese woman presented to our hospital with relapsing respiratory symptoms accompanied by high fever. A detailed interview revealed that the onset of the symptoms occurred shortly after using a humidifier in her home. Her symptoms showed spontaneous improvement soon after admission, and an examination of her bronchoalveolar lavage fluid revealed the specific infiltration of inflammatory cells, which predominantly consisted of lymphocytes. Precipitin testing showed a positive reaction to C. guilliermondii, which was isolated from the home humidifier. Repeated history taking is essential for diagnosing occult respiratory disorders.

Myopathy and eosinophilic pneumonia coincidentally induced by treatment with daptomycin.

A 34-year-old man with 22q11.2 deletion syndrome (DiGeorge syndrome) concurrently suffered from myopathy and eosinophilic pneumonia shortly after receiving daptomycin (DAP) for right-sided infective endocarditis. The simultaneous occurrence of these phenomena in relation to DAP therapy has not been previously well described. An allergic reaction was suspected as a possible etiology of these DAP-related complications. This case highlights the need for close observation in order to detect both musculoskeletal and respiratory disorders from the start of DAP therapy. Physicians should pay more attention to this new drug, which is expected to be frequently used in various clinical settings.

Successful treatment of persistent MRSA bacteremia using high-dose daptomycin combined with rifampicin.

We herein report a case of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia that was successfully treated with combination therapy consisting of high-dose daptomycin (DAP, 10 mg/kg) and rifampicin. The patient's condition was complicated with multiple infectious foci, including an iliopsoas abscess and epidural abscess, as well as discitis and spondylitis at the cervical, thoracic and lumbar levels. Monotherapy treatments with vancomycin, linezolid and usual-dose DAP were all ineffective. It has been shown that usual-dose DAP administration may result in the emergence of a resistant strain and treatment failure. We would like to emphasize the importance of high-dose DAP therapy for MRSA bacteremia, a condition with a potentially high mortality rate.

Fosfomycin for the treatment of prostate infection.

A 69-year-old man with diabetes mellitus was diagnosed with a prostate abscess. Although the pathogen was fluoroquinolone-resistant Escherichia coli and the oral administration of trimethoprim-sulfamethoxazole was initiated, the infection recurred after three months. The antibiotic therapy was subsequently changed to intravenous fosfomycin, and the patient's condition promptly improved. Four weeks of fosfomycin therapy was successfully continued without any adverse events. In the era of antibiotic resistance, revival of forgotten drugs is an important issue for clinicians. Fosfomycin can be applied as an alternative option for prostate infections, considering the remaining susceptibility of multidrug-resistant pathogens to fosfomycin and the good pharmacokinetics of this drug in prostatic tissue.

Recurrent Stenotrophomonas maltophilia bacteremia after iliac crest bone graft harvest.

We describe a rare case of recurrent Stenotrophomonas maltophilia bacteremia in a previously healthy 45-year-old man. The infection was caused by osteomyelitis at the site of an iliac crest bone graft harvest. A genetic analysis using enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) revealed that the blood isolates and pathogens obtained from the surgical wound were identical. Initial treatment with levofloxacin and cefozopran was ineffective, but the patient's infection was successfully treated by long-term administration of latamoxef and trimethoprim-sulfamethoxazole. The present case suggests that attention should be given to the possibility of S. maltophilia infection in any situations.