Whey peptide-based enteral diet attenuated elastase-induced emphysema with increase in short chain fatty acids in mice.

BACKGROUND: Systemic inflammation is present in chronic obstructive pulmonary disease (COPD). A whey peptide-based enteral diet reduce inflammation in patients with COPD, but its effect on COPD development has not been determined. On the other hand, it is known that short chain fatty acids (SCFAs), which are produced by micro-flora in the gut, attenuates bronchial asthma in mice model. METHODS: Mice with elastase-induced emphysema were fed with 1 of 3 diets (control diet, whey peptide-based enteral diet, or standard enteral diet) to determine the effects of whey peptide-based enteral diet on emphysema and on cecal SCFAs. RESULTS: The whey peptide-based enteral diet group exhibited fewer emphysematous changes; significantly lower total cell counts in bronchoalveolar lavage fluid (BALF); and significantly higher cecal SCFA levels than either the control or standard enteral diet groups. The total cell count was inversely correlated with total cecal SCFA levels in these three diet groups. CONCLUSIONS: The whey peptide-based enteral diet attenuates elastase-induced emphysema through the suppression of inflammation in the lung. This may be related to the increase in cecal SCFA.

What determines human body odour?

Human body odour and earwax type are genetically dependent on a single-nucleotide polymorphism (SNP) located in the ABCC11 gene. So far, it still remains to be clear how SNP in the ABCC11 gene is associated with human malodour. In a recent issue of Experimental Dermatology, Baumann et al. propose one of the underlying molecular pathways. Although one of the amino acid conjugated of the odorants, Cys-Gly-3-methyl-3-sulfanylhexanol (3M3SH), was not taken up by the transporter ABCC11, glutathione conjugate of 3MSH (SG-3MSH) was transported by ABCC11. Moreover, SG-3MSH was processed to 3M3SH by γ-glutamyl-transferase 1 (GGT1), which was abundantly expressed in apocrine sweat glands. These findings may pave a way for the pharmacogenetics of human body odour and the development of innovative deodorant products.

Oral administration of a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity for pulmonary arterial hypertension.

BACKGROUND: Continuous administration of prostacyclin has improved the survival of patients with pulmonary arterial hypertension (PAH). However, this treatment has some problems, including its short duration of activity and difficult delivery. Therefore, we developed ONO-1301, an orally active, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. METHODS AND RESULTS: We investigated whether oral administration of ONO-1301 can both prevent and reverse monocrotaline (MCT)-induced PAH in rats. Rats were randomly assigned to receive repeated oral administration of ONO-1301 twice daily beginning either 1 or 8 days after subcutaneous injection of MCT. A control group received oral saline, and a sham group received a subcutaneous injection of saline instead of MCT. MCT-treated controls developed significant pulmonary hypertension. Treatment with ONO-1301 from day 1 or 8 significantly attenuated the increases in right ventricular systolic pressure and the increase in medial wall thickness of pulmonary arterioles. Kaplan-Meier survival curves demonstrated that the effect of ONO-1301 was equivalent to that of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. A single oral dose of ONO-1301 increased plasma cAMP levels for up to 6h. Treatment with ONO-1301 significantly decreased urinary 11-dehydro-thromboxane B2 and increased the plasma hepatocyte growth factor concentration. CONCLUSIONS: Oral administration of ONO-1301 ameliorated PAH in rats, an effect that may occur through cAMP and hepatocyte growth factor.

Difficulties in Differentiating Osteosclerosis in Patients With Multifocal Micronodular Pneumocyte Hyperplasia and Cancer.

A 52-year-old woman with multifocal micronodular pneumocyte hyperplasia in bilateral lungs and multiple sclerotic bone lesions (SBLs) visited our hospital. Tuberous sclerosis complex (TSC) was suspected but did not meet the diagnostic criteria. Ten years later, at age 62, the patient developed ureteral cancer. Cisplatin-containing chemotherapy ameliorated ureteral tumor, concomitant with exacerbation of SBLs. It was difficult to distinguish whether the exacerbation of SBLs was due to exacerbation of TSC or bone metastasis of cancer. The administration of cisplatin made the diagnosis even more difficult because its molecular biological effects can exacerbate the complications of TSC.

A case of diffuse aspiration bronchiolitis due to oesophageal stenosis after radiation therapy.

A 66-year-old woman was hospitalized for recurrent pneumonia twice in 1 year. After treatment for pneumonia, chronic coughing, sputum and low-grade fever continued, so she was referred and admitted to our hospital for investigation. Chest computed tomography revealed a lung infiltrative shadow and diffuse centrilobular micronodules. Histological findings from transbronchial lung biopsy showed chronic inflammation and giant cells in the bronchiole. These findings were compatible with diffuse aspiration bronchiolitis (DAB), which is characterized by chronic inflammation of the bronchioles caused by recurrent aspiration of foreign bodies. Oesophagogastroduodenoscopy revealed stenosis of the oesophageal entrance, which was thought to be caused by radiation therapy for hypopharyngeal cancer 20 years before. Antibiotic treatment ameliorated the centrilobular nodule shadow. After discharge, there was no recurrence. This is the first case report of DAB resulting from oesophageal stenosis associated with hypopharyngeal cancer and will serve as an educational case.

Clinical significance of prostate stem cell antigen expression in non-small cell lung cancer.

OBJECTIVE: Prostate stem cell antigen was originally identified as an overexpressed gene in prostate cancer and its overexpression correlated with disease progression and prognosis. In this study, we investigated the clinical significance and therapeutic potential of prostate stem cell antigen expression in non-small cell lung cancer. METHODS: Prostate stem cell antigen expression was examined by immunohistochemistry in 97 primary tumors and 21 metastatic lymph nodes from non-small cell lung cancer patients who underwent curative resection from January 2001 through March 2003. Therapeutic potential of targeting prostate stem cell antigen was further examined by small interfering RNA method using human lung cancer cell line (A549). RESULTS: Prostate stem cell antigen protein expression was detected in 94 of 97 primary lesions (97%) and all metastatic lymph nodes. Prostate stem cell antigen expression intensity was positively correlated with advanced pathological T-factor and stage (T1 vs. T2-4, P = 0.014; Stage I vs. Stages II-IV, P = 0.029, respectively). The prognosis of patients with low prostate stem cell antigen expression was significantly better than those with high prostate stem cell antigen expression (5-year disease-free survival rate; 90% vs. 53%, P = 0.001). Finally, small interfering RNA-mediated knockdown of prostate stem cell antigen resulted in the inhibition of lung cancer cell growth. CONCLUSIONS: Prostate stem cell antigen is highly expressed in non-small cell lung cancer and may be functionally important for this fatal disease.

Maternal supplementation with Bifidobacterium breve M-16V prevents their offspring from allergic airway inflammation accelerated by the prenatal exposure to an air pollutant aerosol.

Bifidobacterium breve M-16V is a probiotic bacterial strain with efficacy in infants achieved by suppressing T-helper type (Th) 2 immune responses and modulating the systemic Th1/Th2 balance. Exposure to air pollution during pregnancy increases asthma susceptibility in offspring. The aim of this study was to investigate the effects of the maternal intake of B. breve M-16V on susceptibility to asthma accelerated by prenatal exposure to air pollution. The intake of B. breve M-16V in residual oil fly ash (ROFA)-exposed pregnant mice resulted in fewer eosinophils in the bronchoalveolar lavage fluid of neonatal mice and reduced allergic lung inflammation. The expressions of Th2 cytokines including IL-5 and IL-13 were decreased in neonatal mice from ROFA-exposed mothers fed B. breve M-16V. The analysis of fecal microbiota from neonatal mice revealed that the intake of B. breve M-16V by mothers changed the composition of fecal microbiota in neonatal mice, which resulted in a decreased population of Firmicutes. Moreover, several bacterial strains of fecal microbiota from neonatal mice had a strong correlation with Th2 cytokines and histological score. These results suggest that the maternal intake of M-16V might have beneficial effects in neonates by preventing and/or alleviating allergic reactions accelerated by prenatal exposure to air pollution.

Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer.

PURPOSE: The programmed death-1 ligand/programmed death-1 (PD-L/PD-1) pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In this study, we tried to reveal the clinical importance and therapeutic potential of the PD-L/PD-1 pathway in pancreatic cancer, which is one of the most aggressive and intractable malignant tumors. EXPERIMENTAL DESIGN: We used immunohistochemistry to investigate PD-L expression in 51 patients with pancreatic cancer who underwent surgery and explored the therapeutic efficacy of blocking the PD-L1/PD-1 pathway in murine pancreatic cancer in vivo. RESULTS: PD-L1-positive patients had a significantly poorer prognosis than the PD-L1-negative patients, whereas there was no significant correlation of tumor PD-L2 expression with patient survival. PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, particularly CD8(+) T cells. These clinical data have suggested that the PD-L1/PD-1 pathway may be a critical regulator in human pancreatic cancer. Monoclonal antibodies against PD-L1 or PD-1 induced a substantial antitumor effect on murine pancreatic cancer in vivo. PD-L1 blockade promoted CD8(+) T-cell infiltration into the tumor and induced local immune activation. Furthermore, the combination of anti-PD-L1 monoclonal antibody and gemcitabine exhibited a significant synergistic effect on murine pancreatic cancer and resulted in complete response without overt toxicity. CONCLUSION: Our data suggest for the first time that PD-L1 status may be a new predictor of prognosis for patients with pancreatic cancer and provide the rationale for developing a novel therapy of targeting the PD-L/PD-1 pathway against this fatal disease.

Effect of serum leptin levels on hypercapnic ventilatory response in obstructive sleep apnea.

BACKGROUND: Leptin levels have been reported to be higher in patients with obstructive sleep apnea (OSA) than in control subjects with matching age and body mass index (BMI). Although animal studies have shown that leptin augments hypercapnic ventilatory response (HCVR), the effect of leptin on HCVR has not been clarified in OSA. OBJECTIVES: To investigate whether leptin could augment HCVR during wakefulness in patients with OSA. METHODS: Of 134 consecutive patients with OSA, 13 eucapnic and 16 hypercapnic patients with OSA, and 12 control subjects matched for sex, age, and BMI were selected. Fasting serum leptin levels were collected, and HCVR during wakefulness assessed by the slope between minute ventilation and end-tidal PCO(2). RESULTS: There was a significant positive relationship between serum leptin levels and HCVR in the group including control subjects and eucapnic patients with OSA (r = 0.42, p < 0.05). Subgroup analyses suggest that serum leptin levels and HCVR were significantly higher in eucapnic patients with OSA than in control subjects. On the other hand, hypercapnic patients had lower HCVR than eucapnic patients (p < 0.05), whereas serum leptin levels were similar between the two OSA subgroups. CONCLUSION: Leptin levels and HCVR are correlated as long as the eucapnic condition is maintained. We speculate that a stimulating effect of leptin on HCVR may be masked by the hypoventilation state.

Exposure of pregnant mice to an air pollutant aerosol increases asthma susceptibility in offspring.

Air pollution contributes to both exacerbation and development of bronchial asthma. Studies showed that coexposure to air pollution directly promotes sensitization to inhaled allergen in neonatal mice. The aim of this study was to investigate whether prenatal exposure to air pollution could also increase susceptibility to development of asthma in early life. Pregnant female BALB/c mice were exposed to aerosolized leachate of residual oil fly ash (ROFA, 50 mg/ml, 30 min) at 5, 3, and 1 d before delivery. Offspring were treated once at 3 d of age with ovalbumin (OVA, 5 mug) and alum (ip), an intentionally suboptimal dose for sensitization, exposed to aerosolized OVA (1%, 10 min) at 12-14 d or 32-35 d of age, and evaluated 2 d after the final exposure. The offspring of ROFA-exposed mothers (ROFA group) revealed increasing airway hyperresponsiveness (higher enhanced pause [Penh] to methacholine challenge) and elevated substantial numbers of eosinophils in the bronchoalveolar lavage flued (BALF). Histopathology revealed prominent inflammation in the lungs of ROFA group and showed increased allergen-specific IgE and IgG1 levels. Their cultured splenocytes showed an enhanced interleukin (IL)-4/interferon (IFN)-gamma cytokine, indicating Th2 skewed immunity. Data indicate that exposure of pregnant female mice to an air pollutant aerosol increased asthma susceptibility in their offspring.

Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer.

PURPOSE: The negative regulatory programmed death-1/programmed death-1 ligand (PD-1/PD-L) pathway in T-cell activation has been suggested to play an important role in tumor evasion from host immunity. In this study, we investigated the expression of PD-L1 and PD-L2 in human esophageal cancer to define their clinical significance in patients' prognosis after surgery. EXPERIMENTAL DESIGN: PD-L1 and PD-L2 gene expression was evaluated in 41 esophagectomy patients by real-time quantitative PCR. The protein expression was also evaluated with newly generated monoclonal antibodies that recognize human PD-L1 (MIH1) and PD-L2 (MIH18). RESULTS: The protein and the mRNA levels of determination by immunohistochemistry and real-time quantitative PCR were closely correlated. PD-L-positive patients had a significantly poorer prognosis than the negative patients. This was more pronounced in the advanced stage of tumor than in the early stage. Furthermore, multivariate analysis indicated that PD-L status was an independent prognostic factor. Although there was no significant correlation between PD-L1 expression and tumor-infiltrating T lymphocytes, PD-L2 expression was inversely correlated with tumor-infiltrating CD8(+) T cells. CONCLUSIONS: These data suggest that PD-L1 and PD-L2 status may be a new predictor of prognosis for patients with esophageal cancer and provide the rationale for developing novel immunotherapy of targeting PD-1/PD-L pathway.

Dual role of vascular endothelial growth factor in hepatic ischemia-reperfusion injury.

BACKGROUND: Vascular endothelial growth factor (VEGF), a major angiogenic factor, mediates a variety of disease conditions through promotion of angiogenesis. It also plays a critical role as a potent proinflammatory cytokine in a variety of physiologic and pathologic immune responses. In the present study, we evaluated the expression of VEGF in hepatic warm ischemia-reperfusion (I/R) injury and examined the effect of recombinant human (rh)VEGF administration in an established murine model. METHOD: The expression of VEGF in the liver was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry during I/R injury using 70% partial hepatic ischemia model. The effect of rhVEGF administration on I/R injury was evaluated by measuring liver function and histology. In addition, local inducible nitric oxide synthase (iNOS) and endothelial NO synthase expressions were examined to address the underlying mechanisms. RESULTS: The local expression of VEGF was significantly up-regulated at 2 hours after reperfusion after 60 minutes of ischemia compared with that in the naive liver. VEGF was expressed predominantly in CD11b+ cells infiltrating into the ischemic liver. The administration of rhVEGF had a significant protective effect on ischemic injury in the liver. This effect was associated with the up-regulation of iNOS expression in the rhVEGF-treated liver. CONCLUSION: We demonstrate a dual role of VEGF in hepatic warm I/R injury. Although endogenous VEGF is expressed and functional to initiate hepatic I/R injury, exogenous rhVEGF has a beneficial effect on the ischemic liver. These data may provide new insights into the role of VEGF as well as pathophysiology of hepatic I/R injury.

A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection.

BACKGROUND: Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation. Among them, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 3 (CXCR3) have been reported to play important roles in alloimmune responses and may be potential targets for posttransplant immunosuppression. METHODS: Fully major histocompatibility complex (MHC)-mismatched murine cardiac and islet transplant models were used to test the effect in vivo of a novel, small-molecule compound TAK-779 by targeting CCR5 and CXCR3 in acute allograft rejection. An MHC class II mismatched cardiac transplant model was used to evaluate its efficacy in chronic allograft rejection. Intragraft expression of cytokines, chemokines, and chemokine receptors was measured by quantitative real-time polymerase chain reaction and by histological analysis. RESULTS: Treatment of TAK-779 significantly prolonged allograft survival across the MHC barrier in two distinct transplant models. The treatment downregulated local immune activation as observed by the reduced expression of several chemokines, cytokines, and chemokine receptors. Thereby, the recruitment of CD4, CD8, and CD11c cells into transplanted allografts were inhibited. Furthermore, TAK-779 treatment significantly attenuated the development of chronic vasculopathy, fibrosis, and cellular infiltration. CONCLUSIONS: Antagonism of CCR5 and CXCR3 has a substantial therapeutic effect on inhibiting both acute and chronic allograft rejection. CCR5 and CXCR3 are functional in the process of allograft rejection and may be potential targets in clinical transplantation in the future.

Function of the vascular endothelial growth factor receptors Flt-1 and Flk-1/KDR in the alloimmune response in vivo.

BACKGROUND: We have recently reported that vascular endothelial growth factor (VEGF) functions as a proinflammatory cytokine to regulate the trafficking of leukocytes into allografts in the early posttransplant period. VEGF binds two major VEGF receptors: VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR). Here, we wished to investigate the expression and function of VEGF receptors in the process of acute allograft rejection in vivo. METHODS: We performed fully MHC-mismatched C57BL/6 (H-2b) into BALB/c (H-2d) vascularized heterotopic murine cardiac transplants and we examined the expression of VEGF and VEGF receptors by immunohistochemistry during acute allograft rejection. Next, we treated mice with specific neutralizing monoclonal antibodies against murine VEGFR-1 and VEGFR-2 and examined their effect on the development of acute allograft rejection by histology and by analysis of graft survival. The intragraft expression of cytokines and chemokines were also evaluated by quantitative real-time PCR analysis. RESULTS: The expression of VEGF, VEGFR-1 and VEGFR-2 were significantly up-regulated during allograft rejection as compared to isografts. Administration of either anti-VEGFR-1 or anti-VEGFR-2 alone failed to inhibit allograft rejection. However, coadministration of both antibodies together inhibited leukocyte infiltration of allografts and prolonged allograft survival. Furthermore, the effect of VEGFR blockade was associated with the downregulation of intragraft cytokine and chemokine expression. CONCLUSIONS: Our data suggest that VEGF-VEGFR interactions function in the alloimmune response in vivo. Targeting VEGFRs may represent a novel therapy to protect allografts following clinical transplantation.

[A familial case of summer-type hypersensitivity pneumonitis possibly associated with bird breeder's lung diagnosed by bronchoalveolar lavage fluid].

Case 1: A 32-year-old woman had cough and exertional dyspnea in August 2002, and chest computed tomographic scan revealed diffuse centrilobular nodules. Bronchoalveolar lavage fluid (BALF) showed a high proportion of lymphocytes with a decreased CD 4/CD 8 ratio. Transbronchial lung biopsy (TBLB) specimens showed alveolitis. Summer-type hypersensitivity pneumonitis was diagnosed on the basis of positive findings of anti-Trichosporon antibodies in the serum. Case 2: A 64-year-old man, the father of Case 1, also had cough and exertional dyspnea in August 2003. He had been in close contact with pigeons. Chest computed tomographic scan revealed bilateral map-like ground-glass opacities predominantly in the upper lobes. BALF showed a high proportion of lymphocytes with a decreased CD 4/CD 8 ratio. TBLB specimens showed alveolitis, granuloma and Masson body in the air spaces. Specific IgG and IgA antibodies against Trichosporon asahii, IgA antibodies against Trichosporon mucoides, and IgA antibodies against pigeon dropping extracts were found only in the BALF but not in the serum. Although a positive finding of returning-home provocation test was definitive in diagnosing summer-type hypersensitivity pneumonitis, he was also suspected of having bird fancier's lung.

Airway hyperresponsiveness caused by aerosol exposure to residual oil fly ash leachate in mice.

Particulate air pollution is associated with exacerbation of asthma and other respiratory disorders. This study sought to further characterize the pulmonary effects of residual oil fly ash (ROFA), an experimentally useful surrogate for combustion-derived particulates in ambient air. Mice were exposed to aerosols of the soluble leachate of residual oil fly ash (ROFA-s). Physiologic testing of airway function (non invasive plethysmography) showed increased Penh, an index of airway hyperresponsiveness (AHR), in a time- and dose-dependent manner after exposure to ROFA-s. BAL analysis showed a minor influx of neutrophils, which was maximal at 12 h after exposure and essentially resolved by the time point of maximal AHR (48 h after exposure). The AHR caused by ROFA-s was reproduced by a mixture of its major metal components (Ni, V, Zn, Co, Mn, Cu) but not by any individual metal alone. Systemic pretreatment of mice with the antioxidant dimethylthiourea abrogated ROFA-s-mediated AHR. Analysis of mice of varying ages showed that ROFA-s had no marked effect on airway responsiveness of 2-wk-old mice, in contrast to the AHR seen in 3- and 8-wk old mice. ROFA-s-mediated AHR was unchanged in neurokinin 1 receptor knockout mice and in mice treated with an neurokinin antagonist, arguing against a role for this mediator in ROFA-s-mediated effects. Data indicate that ROFA-s mediates AHR in mice through antioxidant-sensitive mechanisms that require multiple metal constituents. Maturational differences in susceptibility to ROFA-induced AHR may be useful for further studies of mechanisms of particle effects.

Two cases of endobronchial neurilemmoma and review of the literature in Japan.

Neurilemmomas are benign tumors which originate from Schwann cells. They rarely occur in the trachea or bronchus. We encountered two cases of endobronchial neurilemmoma and in this context, reviewed 48 cases previously reported in Japan. Neurilemmomas can occur in all regions of the bronchial tree and they often progress into both intraluminal and extraluminal spaces. Incomplete resection results in a local recurrence, despite being rare. As for appropriate therapies, surgery, bronchofiberoptic removal and yttrium aluminum garnet (YAG) laser resection can be chosen depending on the patient's status.

[A case of pleural malignant lymphoma associated with chronic tuberculous pyothorax].

We report a case of pleural malignant lymphoma associated with chronic tuberculous pyothorax. A 67-year-old male was hospitalized because of left lateral chest swelling and pain. He had suffered from pulmonary tuberculosis at the age of six and tuberculous pleurisy at the age of 24. We made a histologic diagnosis of malignant lymphoma diffuse large B-cell type. He was medicated THP-COP (THP, CY, VCR, PSL) therapy and his chest pain and swelling has improved gradually. From the view point of molecular biology, we detected Epstein-Barr virus (EBV) infection in the pyothorax wall. In conclusion, we should be more careful about medical examination in patients with EBV positive tuberculous pyothorax considering the complication of malignant lymphoma.

[A case of AIDS-associated Haemophilus influenzae pneumonia with diffuse reticulonodular shadows].

A 32-year-old male was admitted to our hospital complaining of fever and dyspnea on effort. Laboratory data on admission indicated leukocytosis and elevation of C-reactive protein. A chest radiograph showed diffuse reticulonodular shadows in both lower lung fields, and a chest computed tomography showed centrilobular reticulonodular opacity. Bronchoscopic findings revealed a large amount of slightly yellowish secretion in all bronchi. Cells found in the bronchoalveolar lavage fluid (BALF) included 61% neutrophils. Haemophilus influenzae was isolated from cultures of the BALF and sputum. Transtracheal lung biopsy specimens showed focal infiltration of neutrophils in the alveoli, and the pathological findings in the lung were compatible with bronchiolopneumonia. Since the CD4/CD8 ratio was 0.09 and a positive reaction was obtained for anti-human immunodeficiency virus (HIV) antibody, HIV-associated pneumonia due to H. influenzae was diagnosed. Seven days' administration of cefozopran improved the patient's condition. It is interesting that radiological findings are often unusual in HIV-infected patients with H. influenzae pneumonia.