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.

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.

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.

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.

Acute pulmonary thromboembolism associated with interstitial pneumonia.

A 68-year-old woman, who had been diagnosed as idiopathic interstitial pneumonia, complained of progressive dyspnea on exertion for a week. Although her chest radiograph did not worsen, arterial blood gas findings were markedly worsened. Contrast-enhanced chest computed tomography showed filling defects of the right upper and middle lobe branches of the pulmonary artery. She was diagnosed as having acute pulmonary thromboembolism (APTE). Clinical symptoms and contrast-enhanced chest computed tomography findings were remarkably improved after the treatment with heparin and urokinase. APTE should be considered as a differential diagnosis in patients with interstitial pneumonia who have worsening of respiratory symptoms with unchanged chest radiograph.

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.

Importance of peroxisome proliferator-activated receptor-gamma in hepatic ischemia/reperfusion injury in mice.

BACKGROUND/AIMS: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcriptional factor belonging to the nuclear receptor superfamily. Recent studies have suggested that PPARgamma regulates inflammatory responses and PPARgamma specific agonists have beneficial effects on several disease conditions in the various organs. However, the precise role of PPARgamma in acute liver injury remains unknown. METHODS: We investigated the pathophysiological role of PPARgamma and the effect of the selective PPARgamma agonist, pioglitazone, on the hepatic ischemia/reperfusion (I/R) injury. RESULTS: PPARgamma expression in the liver was upregulated after reperfusion following ischemia. Pioglitazone treatment significantly inhibited hepatic I/R injury as determined by serological and histological analyses. The protective effect was associated with downregulation of the local expression of several potent proinflammatory cytokines, chemokines and adhesion molecules after reperfusion. The neutrophil accumulation was also inhibited by the treatment. Furthermore, the treatment inhibited the induction of apoptosis on hepatocytes. Finally, pioglitazone significantly improved the mouse survival in a lethal model of hepatic I/R injury. CONCLUSIONS: PPARgamma plays an inhibitory role in hepatic I/R injury and the stimulation by selective agonist has a significant beneficial effect. Thus, PPARgamma may be a new therapeutic target for the protection of the liver against acute injury.

Treatment with chondroitinase ABC alleviates bleomycin-induced pulmonary fibrosis.

Pulmonary fibrosis is characterized by an accumulation of inflammatory cells in the lung interstitium, followed by an increased deposition of extracellular matrix. Macrophages play a vital role in this disease by mediating the progression from inflammation to fibrosis, but the mechanisms by which macrophages are retained at these sites are not fully understood. Although the transmigration of leukocytes is regulated by chemokines, glycosaminoglycans modulate the function of chemokines and the migration of leukocytes. Accordingly, we investigated the role of chondroitin sulfate proteoglycans (CSPGs) in a murine bleomycin-induced pulmonary fibrosis models. After intratracheal injection of bleomycin or saline, mice were randomized to receive one intravenous injection and continuous infusion of the CSPG-digesting enzyme chondroitinase ABC (ChABC), or vehicle, for 7 days. CSPGs were readily induced and progressively augmented after the bleomycin challenge. Although CSPGs inhibited the early CCL2-dependent recruitment of macrophages, deposited CSPGs retained macrophages in fibrotic interstitium in a CD44-dependent manner. Treatment with ChABC in vivo dramatically increased survival of the mice and reduced collagen deposition by inhibiting persistent macrophage accumulation. These results indicate a pivotal role for CSPGs in macrophage-mediated lung fibrogenesis and suggest a possible new therapeutic role for ChABC in pulmonary fibrosis.

Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats.

Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 microg x kg(-1) x min(-1)) or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-alpha and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis.

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.

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.

Role of breast milk in a mouse model of maternal transmission of asthma susceptibility.

Epidemiologic data suggest a link between nursing by asthmatic mothers and increased risk of allergy in babies. We sought to experimentally test the potential contribution of breast milk mediator(s) in a mouse model of maternal transmission of asthma risk by evaluating the effect of adoptive nursing on asthma susceptibility in the offspring. We measured airway hyperresponsiveness (AHR) and allergic airway inflammation (AI) after an intentionally suboptimal OVA Ag sensitization, tested the allergen independence of the maternal effect by using a second allergen, casein, for sensitization of the baby mice, and tested the potential role of cytokines by measuring their levels in breast milk. Offspring of asthmatic, but not normal, mothers showed AHR and AI, indicating a maternal transfer of asthma risk. After adoptive nursing, both groups (litters born to asthmatic mothers and nursed by normal mothers, and normal babies nursed by asthmatic mothers) showed AHR (enhanced pause after methacholine aerosol, 50 mg/ml, 3.7 +/- 0.7, 4.2 +/- 0.5, respectively, vs 1.1 +/- 0.1 normal controls, n = 25, p < 0.01) and AI, seen as eosinophilia on histology and bronchoalveolar lavage (40.7 +/- 4.5%, 28.7 +/- 3.7%, vs 1.0 +/- 0.5% normals, n = 25, p < 0.01) after OVA sensitization. Similar results using casein allergen were observed. Multiplex assays for cytokines (IFN-gamma, IL-2, IL-4, IL-5, TNF-alpha, and IL-13) in breast milk were negative. Breast milk is sufficient, but not necessary, to mediate allergen-independent maternal transmission of asthma risk to offspring.

A potent antiangiogenic factor, endostatin prevents the development of asthma in a murine model.

BACKGROUND: Clinical studies suggest a role for angiogenesis in the development and persistence of chronic asthma, but whether angiogenic mediators contribute to acute asthma has not been fully studied. OBJECTIVE: The aim of this study was to investigate a role of vascular endothelial growth factor (VEGF), a major angiogenic and proinflammatory mediator, in allergen-induced acute asthma and to determine whether endostatin/Fc, a potent antiangiogenic factor can attenuate allergic airway responses. METHODS: We sensitized BALB/c mice with ovalbumin. We measured serum VEGF and examined immunoreactive VEGF around the airways 48 hours after the last challenge with either aerosolized PBS or ovalbumin once per day for 3 days. We also treated ovalbumin-sensitized mice with either endostatin/Fc or control fusion protein at the time of challenge with ovalbumin. We analyzed allergic airway responses 48 hours after the last ovalbumin challenge. RESULTS: Ovalbumin challenge induced immunolocalization of numerous VEGF-positive cells around airways and increased serum VEGF levels. Treatment with endostatin/Fc inhibited the airway hyperresponsiveness, pulmonary allergic inflammation, production of ovalbumin-specific IgE, and lung inflammatory mediators. Both VEGF-dependent and independent mechanisms are indicated by results using antibody blockade of VEGF receptors, which caused decreased allergic pulmonary inflammation but did not alter airway hyperresponsiveness or serum IgE levels. CONCLUSION: These data demonstrate for the first time that recombinant endostatin can prevent the development of asthma features in a mouse model and suggest that this class of agents merits further study as novel therapeutics for asthma.

[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.