Shinji Okada

Potential role of interleukin-1 in allergen-induced late asthmatic reactions in guinea pigs: Suppressive effect of interleukin-1 receptor antagonist on late asthmatic reaction

Interleukin (IL)-1 is a pluripotential proinflammatory cytokine and is thought to be involved in the pathogenesis of bronchial asthma and late asthmatic reactions (LARs). To determine whether IL-1 plays a role in LAR, guinea pigs sensitized with Ascaris antigen were used. We evaluated IL-1 production by immunostaining with anti-IL-1 beta antibody and elucidated the action of IL-1 in LAR with recombinant IL-1 receptor antagonist. Immunostaining revealed that IL-1 beta-like immunoreactivity-positive cells increased in the airway walls and in bronchoalveolar lavage fluid after the antigen challenge. IL-1 receptor antagonist protein pretreatment reduced the generation of LAR in terms of pulmonary resistance. IL-1 receptor antagonist protein pretreatment did not change cellular components but reduced the percentage of hypodense eosinophils in bronchoalveolar lavage fluid. We also studied the direct effect of recombinant human IL-1 beta on pulmonary resistance and eosinophil activity measured as released eosinophil peroxidase activity. Recombinant human IL-1 beta did not change pulmonary resistance but primed eosinophils to release eosinophil peroxidase activity in response to platelet activating factor. Therefore these results suggest that IL-1 was produced in sensitized pulmonary tissue of guinea pigs by allergen exposure and played a role in the generation of LAR, at least partially by modulating the activation of eosinophils.

Inhibition of matrix metalloproteinases prevents cardiac hypertrophy induced by β-adrenergic stimulation in rats

Insulin-like growth factor (IGF) -I is one of the candidates for cardiac hypertrophy induced by &bgr;-adrenergic stimulation. However, the mechanisms by which the biologic actions of IGF-I are regulated under this condition remain unclear. IGF-I becomes bioavailable for its receptors upon its dissociation from IGF-binding protein (IGFBP) through IGFBP degradation. Because matrix metalloproteinases (MMPs) have been implicated in the degradation of IGFBPs, the authors investigated the role of MMPs in the regulation of the IGF-I action through the degradation of IGFBPs in cardiac hypertrophy induced by &bgr;-adrenergic stimulation. They examined the expression of MMPs in cardiac tissues of rats infused with isoproterenol (3 mg/kg per day), the effect of a MMP inhibitor, SI-27 (5 mg/rat per day), on cardiac hypertrophy, and the expression of IGF-I and IGFBP-3. MMP-1 and -2 activities increased and IGFBP-3 was degraded in heart hypertrophied by isoproterenol. MMP inhibition caused a regression in the myocyte hypertrophy in association with the suppression of both IGF-I protein in myocytes and the degradation of IGFBP-3 protein. These results suggest that the induction of myocyte hypertrophy by isoproterenol is mediated, at least in part, by a modulation of the IGF-I axis.

The involvement of matrix metalloproteinases in basement membrane injury in a murine model of acute allergic airway inflammation

Background Airway remodelling in asthma such as subepithelial fibrosis is thought to be the repair process that follows the continuing injury as of chronic airway inflammation. However, how acute allergic inflammation causes tissue injury in the epithelial basement membrane in asthmatic airways remains unclear. Matrix metalloproteinases (MMPs) capable of degrading almost all of the extracellular matrix components have been demonstrated to be involved in cell migration through the basement membrane in vivo and in vitro.

Proliferative effects of eosinophil lysates on cultured human airway smooth muscle cells.

Background The hypertrophy/hyperplasia of airway smooth muscle (ASM) cells is one of the characteristic features of bronchial asthma. This structural change leads to the thickening of airway walls resulting in the amplification of airway narrowing. However, the pathogenesis of this structural change has not yet been determined. Eosinophils, which play a pathogenic role in asthma, have been demonstrated to have proliferative effects on fibroblasts and vascular smooth muscle cells.

A cluster of diffuse alveolar hemorrhage cases after the 2011 Tohoku Region Pacific Coast Earthquake

BACKGROUND Diffuse alveolar hemorrhage (DAH) is a clinical syndrome that presents with progressively hemorrhagic bronchoalveolar lavage fluid (BALF) in serial samples and generally has a poor prognosis. The South Miyagi Medical Center, located on the inland side of southern Miyagi Prefecture, documented an increase in the number of patients with DAH after the 2011 Tohoku Region Pacific Coast Earthquake. METHODS We describe the clinical features of post-earthquake DAH in comparison to pre-earthquake DAH. We analyzed the data of the DAH patients we have been able to follow for at least 6 months since we started performing bronchoscopy and bronchoalveolar lavage (BAL) for all patients with interstitial lung disease in August 2009 until September 2011, and separated these patients into pre- and post-earthquake groups according to the earthquake date of March 11, 2011. RESULTS Post-earthquake DAH patients tended to test positive for infectious agents and showed higher serum IgE titers, with BALF that exhibited a tendency to higher silica concentrations. Post-earthquake DAH generally had a better prognosis than pre-earthquake DAH. CONCLUSIONS In describing the clinical features of post-earthquake cases of DAH, this report documents the possibility of an infection- and/or dust-induced, partially allergic, and relatively benign form of DAH.

Possible mechanisms of airway hyperresponsiveness after late asthmatic response in guinea pigs.

To elucidate the mechanism of airway hyperresponsiveness after late asthmatic response (LAR), we analyzed bronchoalveolar lavage fluid (BALF) and examined the airway smooth muscle contractility to acetylcholine (ACh). On day 1 after LAR, there was a significant positive correlation between the number of neutrophils in BALF and the increase in airway responsiveness after LAR (r = 0.82, p < 0.01). In the in vitro study, the dose response curve to ACh was significantly shifted to the left after removal of the epithelium in control guinea pigs. However, in hyperresponsive animals after LAR, removal of the epithelium had no significant effect on ACh-induced response. These results indicate that infiltration of neutrophils and other inflammatory cells induce epithelial damage and hence the development of airway hyperresponsiveness after LAR.

Adjuvant Effect of lnterleukin-1 on the Development of Late Asthmatic Response in Guinea Pigs

The adjuvant effect of silica and IL-1 in the development of late asthmatic responses (LARs) in guinea pigs was studied. Different doses of silica or recombinant human (rh) IL-1 (1 microgram) with Ascaris suum were used for the immunization. The serum IL-1 concentration was measured after the immunization. One week after the immunization, antigen was challenged and respiratory resistance (Rrs) was measured. Rrs increased silica dose dependently in the late phase, and the increment of Rrs in the late phase was significantly correlated with the serum IL-1 concentration (p < 0.05). In addition, rhIL-1 administration showed an increase in Rrs at the late phase. Antigen-specific IgE and IgG1 were also measured and were increased in guinea pigs immunized both with silica and rhIL-1.

Improving Physical Activity Ensures the Long-Term Survival of Pneumonia Patients in a Super-Aged Society: A Retrospective Study in an Acute-Care Hospital in Japan

Pneumonia is the third largest cause of death in Japan. Chest physicians have been struggling to improve the outcome of pneumonia treatment in acute care settings. However, a poor long-term prognosis after pneumonia has not been well recognized. Furthermore, the factors related to the poor prognosis, especially the possible involvement of senescence-related disability, have not been identified. In this study, long-term outcomes after discharge from hospital were retrospectively analyzed to identify factors related to the poor long-term prognosis. Outcomes of 958 pneumonia patients who were discharged from South Miyagi Medical Center (Miyagi, Japan) from June 1, 2008 to March 31, 2014 were determined through patient surveys or medical record reviews on September 26, 2014. Survival curves were constructed and compared according to various factors. Multivariate analysis revealed that all levels of decrease in physical activity, an age of 80 years old or more, the most severe status in Japanese Respiratory Society pneumonia severity grading system, the presence of antibiotic-resistant bacteria, and comorbid malignancy significantly reduced long-term survival. The effects of dementia, neuromuscular disease, heart disease, and nursing care residency on long-term survival were detected only with univariate analysis. Physical activity influenced the acute-phase and the long-term prognosis of pneumonia. This report provides information to assist physicians in giving better suggestions to disabled older patients when choosing pneumonia treatment options. In conclusion, we propose that death related to pneumonia can be prevented in the same way as non-communicable diseases by improving physical activity.

Prolongation of neutrophil survival by the culture supernatant of Pseudomonas aeruginosa.

Background and objectives:  The pathogenesis of airway inflammation in diffuse panbronchiolitis (DPB) is unknown. Neutrophil survival‐enhancing activity, partially mediated by granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), has been shown in the sputum from DPB patients. This study investigated the mechanisms of GM‐CSF expression in the airways of DPB patients. This involved examining the effects of mucoid Pseudomonas aeruginosa strains derived from chronically colonized patients with DPB on neutrophil survival and GM‐CSF expression.

Pulmonary Hypertension and Its Response to Treatment in a Patient With Kyphosis-related Alveolar Hypoventilation

Pulmonary hypertension (PH) with kyphoscoliosis-related alveolar hypoventilation is uncommon, so little is known about the effectiveness of treatments for this condition. A 66-year-old man with kyphosis who had been treated with nocturnal noninvasive positive-pressure ventilation developed PH with a mean pulmonary arterial pressure (PAP) of 32 mmHg and a pulmonary vascular resistance (PVR) of 5.95 Wood units. After addition of oxygen therapy and tadalafil, his condition improved. One year later, his mean PAP and PVR were 25 mmHg and 3.62 Wood units, respectively. This case shows the therapeutic potential of vasoactive medications for alveolar hypoventilation-related PH.