Role of insulin-like growth factor-I in allergen-induced airway inflammation and remodeling

Insulin-like growth factor (IGF)-I is known to act on fibroblasts as a progression factor to push cells toward proliferation and activation to synthesize collagen. Subepithelial fibrosis, collagen deposition at the lamina reticularis, is part of the process of so-called remodeling and is a characteristic finding in the asthmatic airway. To study the role of IGF in the evolution of asthma, we used a model that involved immunization of mice with ovalbumin and alum, followed by an inhaled challenge of ovalbumin. IGF-I neutralizing antibody was continuously infused with an osmotic pump. Pulmonary function was analyzed using whole-body plethysmography before and after acetylcholine administration. It was found that OVA inhalation induced IGF-I expression at the site of the airway. IGF-I neutralizing Ab inhibited the elevation of airway resistance, airway inflammation, and an increase in airway wall thickening. The depression of ICAM-1 expression was accompanied by a diminution in airway inflammation. In conclusion, these results suggest that IGF-I is likely to be an important mediator of inflammation and remodeling in the asthmatic airway.     

JNK and PI3k/Akt signaling pathways are required for establishing persistent SARS-CoV infection in Vero E6 cells

Persistence was established after most of the SARS-CoV-infected Vero E6 cells died. RNA of the defective interfering virus was not observed in the persistently infected cells by Northern blot analysis. SARS-CoV diluted to 2 PFU failed to establish persistence, suggesting that some particular viruses in the seed virus did not induce persistent infection. Interestingly, a viral receptor, angiotensin converting enzyme (ACE)-2, was down-regulated in persistently infected cells. G418-selected clones established from parent Vero E6 cells, which were transfected with a plasmid containing the neomycin resistance gene, were infected with SARS-CoV, resulting in a potential cell population capable of persistence in Vero E6 cells. Our previous studies demonstrated that signaling pathways of extracellular signal-related kinase (ERK1/2), c-Jun N-terminal protein kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3'-kinase (PI3K)/Akt were activated in SARS-CoV-infected Vero E6 cells. Previous studies also showed that the activation of p38 MAPK by viral infection-induced apoptosis, and a weak activation of Akt was not sufficient to protect from apoptosis. In the present study, we showed that the inhibitors of JNK and PI3K/Akt inhibited the establishment of persistence, but those of MAPK/ERK kinase (MEK; as an inhibitor for ERK1/2) and p38 MAPK did not. These results indicated that two signaling pathways of JNK and PI3K/Akt were important for the establishment of persistence in Vero E6 cells.     

A neural mechanism of hierarchical discrimination of odors in the olfactory cortex based on spatiotemporal encoding of odor information

We propose a neural mechanism for discrimination of different complex odors in the olfactory cortex based on the dynamical encoding scheme. Both constituent molecules of the odor and their mixing ratios are encoded simultaneously into a spatiotemporal activity pattern (limit cycle attractor) in the olfactory bulb [Hoshino O, Kashimori Y, Kambara T (1998) Biol Cybern 79:109–120]. We present a functional model of the olfactory cortex consisting of some dynamical mapping modules. Each dynamical map is represented by itinerancy among the limit cycle attractors. When a temporal sequence of spatial activity patterns corresponding to a complex odor is injected from the bulb to the network of the olfactory cortex, the neural activity state of each mapping module is fixed to a relevant spatial pattern injected. Recognition of an odor is accomplished by a combination of firing patterns fixed in all the mapping modules. The stronger the response strength of the component, the earlier the component is recognized. The hierarchical discrimination of an odor is made by recognizing the components in order of decreasing response strengths. Received: 28 November 1998 / Accepted in revised form: 17 December 1999     

Immune gene therapy of experimental mouse brain tumor with adenovirus-mediated gene transfer of murine interleukin-4

 We examined the antitumor activity of replication-deficient adenoviral vectors carrying the murine interleukin-4 (IL-4) gene (AdCIL4) using a syngeneic brain tumor model in mice. Mice implanted with malignant astrocytoma cells infected with AdCIL4 survived significantly longer than those in the control groups. Immunocytochemical analysis of the tumors showed that AdCIL4 caused the strong up-regulation of MHC class II antigen expression by the tumor cells and macrophages, and consequent infiltration by CD8⁺ T lymphocytes. This study demonstrates the efficacy of IL-4 gene transfection mediated by adenoviral vectors for intracerebral tumor and characterizes the immunoreaction caused by AdCIL4. Received: 27 August 1999 / Accepted: 12 November 1999     

Electron microscopy examination of galanin-like peptide (GALP)-containing neurons in the rat hypothalamus

Galanin-like peptide (GALP) is a novel peptide which is isolated from the porcine hypothalamus. GALP-containing neurons are present in the arcuate nucleus (ARC), being particularly densely concentrated in medial posterior regions. To observe the ultrastructure and synaptic relationships of GALP-containing neurons in the ARC, light and immunoelectron microscopy techniques were used. At the light microscope level, GALP-containing neurons were observed distributed rostrocaudally throughout the ARC, with the majority present in the posterior, periventricular zones. At the electron microscope level, many immunopositive dense-cored vesicles were evident in the perikarya, dendrites and axon terminals of the GALP-containing neurons. Furthermore, these neurons received synapses from immunonegative axon terminals that were symmetric in the case of synapses made on perikarya, and both asymmetric and symmetric for synapses made on dendrites. Axon terminals of GALP-containing neurons often made synapses on immunonegative dendrites. Such synapses were all symmetric. Synapses were also found between axon terminals and perikarya as well as dendrites of GALP-containing neurons. These findings suggest that the physiological role of the GALP-containing neurons in the ARC is based on complex synaptic relationships between GALP-containing neurons and either GALP-immunopositive or -immunonegative neurons.     

Central administration of phosphatidylserine attenuates isolation stress-induced behavior in chicks

The present study investigated whether centrally administered phosphatidylserine (PS) could modify the behavior of chicks under isolation-induced stress. Isolation stress-induced vocalization and spontaneous activity for 10 min, which were attenuated by intracerebroventricular (i.c.v.) injection of PS. The effect of PS was compared with other phospholipids or L-serine, a constituent of PS. Phosphatidylcholine (PC) had no effect on these behavior, but phosphatidylethanolamine (PE) significantly increased vocalizations and spontaneous activity compared with PS. L-Serine similarly decreased isolation-induced vocalizations and spontaneous activity. To clarify the mechanism by which central PS attenuates isolation-induced stress behavior, the contribution of the acetylcholine (ACh) receptor (AChR) was also investigated. PS was co-injected i.c.v. with the muscarinic AChR (M-AChR) antagonist scopolamine or the nicotinic AChR (N-AChR) antagonist hexamethonium. The suppression of vocalizations and spontaneous activity by PS was partially attenuated by scopolamine, but not hexamethonium. These findings indicate that isolation-induced stress behavior are attenuated by PS, acting partially through the M-AChR.