Three cases in which drug-induced hyponatremia was improved by replacing carbamazepine with lacosamide.

Carbamazepine often causes drug-induced hyponatremia. Hyponatremia due to carbamazepine may be improved by changing to the same mechanism of action, lacosamide.

Assessment of oxidative stress in autism spectrum disorder using reactive oxygen metabolites and biological antioxidant potential.

There are several studies on oxidative stress of Autism Spectrum Disorder (ASD), but in these cases there is no study to measure oxidative stress and antioxidant capacity at the same time or studies considering childhood development. Therefore, this study comprehensively assessed the level of oxidative stress in ASD children by simultaneously measuring reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP). The subjects were Japanese, 77 typical development (TD) children, 98 ASD children, samples were plasma. The subjects were divided into age groups: toddlers/preschool age (2-6 years) and school age (7-15 years), to compare the relationships among the d-ROMs levels and BAP/d-ROMs ratios. Furthermore, the correlations between the Parent-interview ASD Rating Scales (PARS) scores and the measured values were analyzed. The levels of d-ROMs were significantly higher in the ASD (7-15 years) than in TD (7-15 years). The PARS scores were significantly higher in the ASD and were significantly correlated with d-ROMs levels. These results suggested that d-ROMs and BAP/d-ROMs ratios could be objective, measured indicators that could be used in clinical practice to assess stress in ASD children.

Evaluation of the efficacy of drug treatment based on measurement of the oxidative stress, using reactive oxygen metabolites and biological antioxidant potential, in children with autism spectrum disorder and attention deficit hyperactivity disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder, mainly characterized by impairment of social communication and restricted interests. ASD is frequently accompanied by attention deficit hyperactivity disorder (ADHD), which is characterized by carelessness, hyperactivity and impulsivity (ASD/ADHD). It has been suggested that ASD and ADHD are associated with oxidative stress, that is, that patients with ASD/ADHD are in a state of increased oxidative stress. There are currenr tly no objective or biological test criteria for evaluating the efficacy of drug therapy in these patients. The purpose of this study was to evaluate whether oxidative stress markers [serum reactive oxygen metabolites (d-ROMs) levels and biological antioxidant potential (BAP)] can be used as objective indicators for evaluating the efficacy of drug treatment in ASD/ADHD patients. METHODS: The subjects of this study subjects were 50 Japanese patients with ASD/ADHD aged 4 to 14 years old. Serum samples were obtained from the patients to measure the serum levels of d-ROMs and the serum BAP. The study subjects were divided into two age groups: preschool children (4 to 6 years old) and school-age children (7 to 14 years old), and the serum levels of d-ROMs, serum BAP, serum BAP/d-ROMs ratio (hereinafter, the prefix serum will be dropped), and scores on the Parent-interview ASD Rating Scales-Text Revision (PARS-TR) and ADHD Rating Scale (ADHD-RS) were determined before and after drug therapy and compared between the two groups. In addition, changes in the d-ROMs, BAP and BAP/d-ROMs ratio and changes in the scores on the PARS-TR and ADHD-RS after treatment were also analyzed. RESULTS: Significant decrease of the d-ROMs, BAP, and scores on the PARS-TR and ADHD-RS, with a significant increase of the BAP/d-ROMs ratio, was observed after treatment. In addition, a significant correlation was observed between the changes in the d-ROMs and changes in the scores on the PARS-TR and ADHD-RS after treatment in the school-age ASD/ADHD children. CONCLUSION: Our results suggest the possibility that the serum level of d-ROMs may be useful as an objective assessment marker to supplement the subjective assessment of the effects of drug treatment in school-age children with ASD/ADHD.

Evaluation of oxidative stress and antioxidant capacity in healthy children.

BACKGROUND: Measurement of the levels of the derivatives of reactive oxygen metabolites (d-ROMs) and of the biological antioxidant potential (BAP) enables simultaneous assessment of oxidation degree and antioxidant capacity, using the same sample and testing equipment. At present, reference values of healthy adults are clarified, but the reference value of healthy children is unknown. This study was undertaken to clarify the age-related changes and the reference values of d-ROMs and BAP in healthy children. METHODS: The study population consisted of 77 children, ranging in age from 2 to 15 years, in normal mental and physical health as examined by a pediatrician, and seven healthy adult volunteers. Serum samples were obtained from the subjects for assay. Using these samples, d-ROMs and BAP values were measured, and the relationship with age was analyzed. RESULTS: The d-ROMs level decreased as the age increased, while the BAP showed no correlation with the age. The d-ROMs level was significantly higher in 2-6 years group than in 7-11 years group, 12-15 years group, or healthy adults group. The BAP/d-ROMs ratio, an index of antioxidant capacity, increased significantly with higher age. CONCLUSION: This study was carried out for the first time in healthy children in oxidative stress assessment using d-ROMs and BAP. In the infancy 2-6 years, the d-ROMs value was significantly higher and the BAP/d-ROMs ratio was significantly lower. From this, it was suggested that age should be considered when performing oxidative stress assessment using d-ROMs and BAP in children.

Influence of nanoparticle size on the skin penetration, skin retention and anti-inflammatory activity of non-steroidal anti-inflammatory drugs.

BACKGROUND: This study aims to evaluate the influence of nanoparticle size on the in vitro percutaneous penetration and retention and in vivo anti-inflammatory efficacy of percutaneously delivered non-steroidal anti-inflammatory drugs. METHODS: Indomethacin, ketoprofen and piroxicam were incorporated into nanoparticles. The nanoparticles, or the bulk-drug equivalents, were suspended in a hydrophilic ointment and compared for their ability to facilitate percutaneous drug penetration and retention in vitro. The formulations were applied cutaneously in a carrageenan-induced footpad inflammation model (acute inflammation) and an adjuvant-induced arthritis model (chronic inflammation) in rats and were assessed for their anti-inflammatory efficacy and potency. RESULTS: The nanoparticle formulations demonstrated a substantially smaller particle size compared with the bulk-drug formulations. The nanoparticles notably increased drug penetration and retention in vitro. In both the acute and chronic inflammation models, the nanoparticle formulations demonstrated significantly higher anti-inflammatory activity than that of their corresponding bulk-drug formulation at an equivalent dose, and produced better overall healing. CONCLUSION: The nanoparticle formulations are highly effective as percutaneous drug carriers, and demonstrate that decreasing particle size leads to increased efficacy and potency. The exploitation of such nanotechnology could drive the development of more effective percutaneous therapeutics.

Impact of Oxidative Stress and Newer Antiepileptic Drugs on the Albumin and Cortisol Value in Severe Motor and Intellectual Disabilities With Epilepsy.

BACKGROUND: Epilepsy is a common complication in patients with severe motor and intellectual disabilities (SMID). There are no reports as yet of the effects of these medications in vivo other than their epileptic efficacy. The purpose of this study was to clarify the effects of the newer antiepileptic drugs (AEDs) on the blood biochemical parameters and oxidative stress in SMID with epilepsy by comparing the therapeutic effects between a group of patients receiving lamotrigine (LTG) and levetiracetam (LEV) in addition to the conventional AEDs (newer AED group) and a group receiving conventional AEDs alone (old AED group). METHODS: The study population consisted of 44 SMID patients with epilepsy, of which 23 were allocated to the newer AED group and 21 were allocated to the old AED group. In the newer AED group, measurements of the reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP) and serum albumin were carried out at the following two time points: 1 week before and 1 year after the start of administration of the newer AEDs. In the old AED group, measurements of the same variables were performed at two time points 1 year apart. RESULTS: A significant decrease of the d-ROM levels and a significant increase of the BAP were noted in the newer AED group. A significant elevation of the serum albumin was also evident. In the old AED group, a significant increase of the d-ROMs levels was noted at the second measurement. Cortisol levels which have been described to be related to the albumin, revealed a significant decrease of the serum cortisol in relation to elevation of serum albumin in the newer AED group. CONCLUSIONS: The present study results suggest that the addition of newer AEDs reduces the oxidative stress load and improves the antioxidant potential of the body. Furthermore, the present data also demonstrate that the newer AEDs have indirect impact on biological parameters.

A study of oxidative stress and the newer antiepileptic drugs in epilepsy associated with severe motor and intellectual disabilities.

BACKGROUND: Patients with severe motor and intellectual disabilities (SMID) are those who have both severe intellectual disabilities and severe physical disabilities. Intractable epilepsy is often associated with SMID. The purpose of this study was to elucidate the relationship between epilepsy associated with SMID and oxidative stress, and to clarify the safety and efficacy of the newer antiepileptic drugs (newer AEDs), lamotrigine and levetiracetam. METHODS: This study was conducted in 27 SMID patients with epilepsy who were treated with the newer AEDs. The patient characteristics and the safety and efficacy of the newer AEDs were investigated. The reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP) levels were measured as indicators of the degree of oxidative stress. The relationship between the investigation results (the patient characteristics, and the safety and efficacy of the newer AEDs) and the results of measurements of the d-ROMs/BAP were analyzed. RESULTS: All the patients who discontinued the newer AEDs had abnormal plasma d-ROM levels. In addition, all the patients who developed adverse events also had abnormal d-ROM levels. Furthermore, there was a trend toward a lower response rate in patients with higher plasma d-ROM levels. CONCLUSION: The results of this study suggested that d-ROM levels are useful for predicting the safety and efficacy of the newer AEDs (lamotrigine, levetiracetam) in SMID patients with intractable epilepsy. Therefore, d-ROMs could be important biomarkers for determining the safety and efficacy of drug therapy in SMID patients with epilepsy.

Oxidative Stress Measurement and Prediction of Epileptic Seizure in Children and Adults With Severe Motor and Intellectual Disabilities.

BACKGROUND: The medical care of severe motor and intellectual disabilities (SMID) depends on the empirical medical care. Epileptic seizure specific to SMID is difficult to suppress using anti-epileptic drugs, and its tendency to persist for long periods poses an issue. The present study was undertaken to evaluate the relationship between epileptic seizure in cases with SMID and oxidative stress in the living body by examining endogenous antioxidants, the degree of oxidation (reactive oxygen metabolites (d-ROMs)), and the biological antioxidant potential (BAP) as indicators. METHODS: Target patients were 43 SMID epilepsy patients. Blood was sampled before breakfast and medication. As for the specimen, d-ROMs and BAP were measured using the free radical analyzer. RESULTS: The present study did not reveal any correlation between endogenous antioxidants (albumin) and the frequency of epileptic seizures. On the other hand, d-ROMs were correlated with the frequency of epileptic seizure. In particular, strong correlations between the frequency of epileptic seizures and the d-ROMs/BAP ratio as well as the BAP/d-ROMs ratio were noted. CONCLUSIONS: These results indicate that the use of d-ROMs and BAP as biomarkers can provide a tool for predicting the prognosis of epileptic seizures in patients with SMID.

Ameliorative effects of Eriobotrya japonica seed extract on cellular aging in cultured rat fibroblasts.

To investigate the effects of Eriobotrya japonica seed extract (ESE) on cellular aging, intracellular calcium homeostasis in young and senescent cells was analyzed using a rat fibroblast culture as an in vitro model system and a calcium imaging technique. The application of bradykinin (BK) transiently elicited intracellular calcium ion (Ca(2+)) increased in most of the young fibroblasts, whereas these responses were scarcely observed or were significantly attenuated in senescent cells. However, the long-term treatment of senescent cells with ESE (for 7 days) dose-dependently increased the amplitude of BK-induced responses and the percentage of BK-responding cells. In particular, most senescent cells could respond to BK with long-term treatment with ESE (1.0% or 2.0%), an effect that reinstated the percentage of BK-responding cells to the same level as that in young cells. The effects of ESE on amplitude or percentage of responding cells were not observed in young cells. Moreover, the time to half decay, which was significantly longer in senescent cells than that in young cells, was shortened in senescent cells with long-term treatment with ESE. These results suggest that treatment with an adequate concentration of ESE renders BK-induced Ca(2+) dynamics in senescent cells similar to those in young cells. Therefore, ESE can retard and/or protect against cellular aging and may be useful for elucidating the antiaging processes.

Eriobotrya japonica seed extract and deep sea water protect against indomethacin-induced gastric mucosal injury in rats.

We have previously reported that Eriobotrya japonica seed extract (ESE) is effective for the treatment of various gastric mucosal injuries. For the pharmaceutical preparation of ESE, we are evaluating deep sea water (DSW), which contains trace elements and has a homeostasis-enhancing effect, as the solvent. In this study, we prepared DSW containing ESE (ESE + DSW) and evaluated its usefulness for the prevention of gastric mucosal injuries using non-steroidal anti-inflammatory drug-induced acute gastric mucosal injury models in male Wistar/ST rats. Gastric mucosal injury models were prepared by administering indomethacin at 30 mg/kg orally to the rats after a 24-h fast. ESE was prepared by a routine procedure and administered at the same concentration as in the administration to humans. The rats were divided into the following 6 groups: ESE, DSW, ESE + DSW, tap water (control), rebamipide (positive control), or untreated. Gastric mucosal injuries were evaluated by measuring the injury area, lipid peroxide (LPO) level, antioxidative enzyme level, and volume of mucus. The injury area and LPO levels in plasma and gastric tissue were significantly reduced in the ESE and ESE + DSW groups compared with the control and DSW group. The plasma and gastric tissue antioxidative enzyme levels were significantly higher in the ESE and ESE + DSW groups than in the control group. These results suggest that DSW, when combined with ESE, inhibits antioxidative enzymes, and enhances the gastric mucosal protecting effect of ESE.

Immunomodulatory effect of Eriobotrya japonica seed extract on allergic dermatitis rats.

We examined the immunomodulatory effect of Eriobotrya japonica seed extract (ESE) on rat allergic dermatitis elicited by repeated dinitrofluorobenzene (DNFB) application on the ear. Oral administration of ESE significantly inhibited development of allergic dermatitis based on lower ear thickness and serum immunoglobulin E (IgE) levels. Th1 cytokine interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), Th2 cytokine interleukin-4 (IL-4) and interleukin-10 (IL-10) in the lesional skin were determined. Oral administration of ESE significantly decreased IL-4 while significantly increasing IL-10 in lesional skin, and the lower levels of IFN-gamma and IL-2 were reversed by oral administration of ESE. The infiltration of eosinophils in the lesional skin was decreased by oral administration of ESE. These results suggested that ESE exerts anti-allergic actions by improving the balance of Th1/Th2 in allergic dermatitis.

Effects of Eriobotrya japonica seed extract on oxidative stress in rats with non-alcoholic steatohepatitis.

OBJECTIVES: Non-alcoholic steatohepatitis is associated with the deposition of lipid droplets in the liver, and is characterised histologically by the infiltration of inflammatory cells, hepatocellular degeneration and liver fibrosis. Oxidative stress may play an important role in the onset and deterioration of non-alcoholic steatohepatitis. We previously reported that an Eriobotrya japonica seed extract, extracted in 70% ethanol, exhibited antioxidant actions in vitro and in vivo. In this study, we examined the effect of this extract in a rat model of non-alcoholic steatohepatitis. METHODS: The seed extract was given in the drinking water to fats being fed a methionine-choline-deficient diet for 15 weeks. KEY FINDINGS: Increases in alanine aminotransferase and aspartate aminotransferase levels were significantly inhibited in rats fed the seed extract compared with the group on the diet alone. Formation of fatty droplets in the liver was also inhibited. Antioxidant enzyme activity in liver tissue was higher than in the diet-only group and lipid peroxidation was reduced compared with rats that also received the extract. Expression of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal was lower in the rats given the seed extract than in the diet-only group. In the former, liver tissue levels of transforming growth factor-beta and collagen were also decreased. CONCLUSIONS: Thus, the E. japonica seed extract inhibited fatty liver, inflammation and fibrosis, suggesting its usefulness in the treatment of non-alcoholic steatohepatitis.

Animal studies supporting the inhibition of mast cell activation by Eriobotrya japonica seed extract.

OBJECTIVES: The potent antioxidant activity of Eriobotrya japonica seed extract (ESE) and its usefulness in the prevention and treatment of various disorders has been reported previously. Its antioxidant activity associated with beta-sitosterol and polyphenols contained in the extract was also validated. In this study, anti-allergic activity of Eriobotrya japonica seed extract was investigated. METHODS: The inhibition of histamine release-mediated type 1 allergy by Eriobotrya japonica seed extract was used as an index. KEY FINDINGS: The administration of this extract inhibited histamine release from rat mast cells, suggesting its usefulness in allergic disease treatment. In an experiment using a guinea-pig allergic rhinitis model, this extract reduced the frequency of sneezing and nose-scratching. CONCLUSIONS: These results suggest that Eriobotrya japonica seed extract may contribute to the relief of allergic disease-related symptoms.

Gastroprotective activity of Eriobotrya japonica seed extract on experimentally induced gastric lesions in rats.

The effect of Eriobotrya japonica seed extract (ESE) prepared with 70% ethanol on gastric mucosal injury was investigated. Six experimental models with different action mechanisms were used for the evaluation. Three concentrations of ESE were prepared for each model. ESE administration was initiated 14 days before induction of gastric mucosal injury, and its effect was investigated. ESE inhibited formation of gastric mucosal injury.

Effect of orally administered Eriobotrya japonica seed extract on allergic contact dermatitis in rats.

The anti-allergic activity of Eriobotrya japonica seeds extract (ESE) was investigated. Oral administration of ESE dramatically inhibited ear swelling due to allergic contact dermatitis caused by repeated application of two antigens, 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) and dinitrofluorobenzene (DNFB), respectively. The increase of histamine content in inflamed ear tissue induced by oxazolone and DNFB was significantly antagonized by orally administered ESE. Eosinophil peroxidase and myeloperoxidase activity in both models was suppressed by orally administered ESE. Tumour necrosis factor-alpha in the inflamed region caused by repeated application of DNFB was also significantly suppressed. The findings suggest that ESE may be effective for treating allergic contact dermatitis.

Scavenging of reactive oxygen species by Eriobotrya japonica seed extract.

We have clarified that Eriobotrya japonica seed extract has strong antioxidative activity, and is effective for the prevention and treatment of various diseases, such as hepatopathy and nephropathy. In this study, to investigate the influences of components of Eriobotrya japonica seed extract on its antioxidative activity, extracts were prepared using various solvents (n-hexane (Hex), ethyl acetate (EtOAc), n-butanol (n-BuOH), methanol (MeOH) and H2O) and the antioxidative activity of the solvent fractions and components was evaluated based on the scavenging of various radicals (DPPH and O2(-)) measured by the ESR method and the inhibition of Fe3+-ADP induced NADPH dependent lipid peroxidation in rat liver microsomes. The radical scavenging activities and inhibitory activities on lipid peroxidation differed among the solvent fractions and components. In the n-BuOH, MeOH and H2O fractions, radical scavenging activity and inhibitory activity on lipid peroxidation were high. In addition, these fractions contained abundant polyphenols, and the radical scavenging activity increased with the polyphenol content. In the low-polar Hex and EtOAc fractions, the radical scavenging activity was low, but the lipid peroxidation inhibition activity was high. These fractions contained beta-sitosterol, and the inhibitory activity on lipid peroxidation was high. Based on these findings, the antioxidative activity of Eriobotrya japonica seed extract may be derived from many components involved in a complex mechanism, resulting in high activity.

The effect of Eriobotrya japonica seed extract on oxidative stress in adriamycin-induced nephropathy in rats.

Eriobotrya japonica has been used as a medicinal plant for a long time, and its leaves are known to have many physiological actions such as anti-inflammatory, antitussive, and expectoran. In contrast, Eriobotrya japonica seeds are only known to contain amygdalin, and almost no investigations of its pharmacological action have been performed. Moreover, some anticancer agents such as adriamycin cause renal disorders as an adverse effect, and the mechanism of the adverse effect is considered to involve oxidative stress. We have reported that Eriobotrya japonica seed extract has an inhibitory effect on liver disorders. In this study, we prepared a 70% ethanol extract of Eriobotrya japonica seeds and administered the extract to rats with renal disorder induced by a single administration of 7 mg/kg body weight adriamycin, and investigated the usefulness of the extract. Increases in indices of renal function, plasma urea nitrogen, were significantly inhibited in rats treated with the Eriobotrya japonica extract compared to rats treated with tap water. In addition, the renal tissue level of reduced glutathione was significantly high in rats that ingested the extract, while the lipid peroxide levels in plasma and renal tissue were significantly low. However, no effect on renal tissue antioxidative enzymes was observed, suggesting that Eriobotrya japonica seed extract has direct antioxidative action. Based on these findings, Eriobotrya japonica seed extract may be effective in reducing the oxidative stress of adriamycin-induced renal disorder. Therefore, ingestion of Eriobotrya japonica seed extract may contribute to a reduction of the adverse effects of adriamycin.

Difference between deep seawater and surface seawater in the preventive effect of atherosclerosis.

Using surface and deep seawater collected in the sea area of Muroto Cape (Kochi, Japan), desalinated drinking samples of about 1200 hardness were prepared and examined for the effects on the prevention of atherosclerosis in dietary induced hyperlipidemia rabbits. The plasma LDL cholesterol level was lower in the deep seawater group than in the surface seawater group. GPx activity was significantly higher in the deep seawater group than in the control group, while there was no difference between the surface seawater and control groups. The level of LPO was also significantly lower in the deep seawater group than in the control group. The Sudan IV lipid stained area ratio on the inner surface of the aorta was significantly lower in the deep seawater groups than in the control group, while there was no difference between the surface seawater and control groups. The oil red O stained cross section of the aorta in the control and surface seawater administration group foam cells had accumulated to form thick layers, while in the deep seawater administration group, the degree of their accumulation was very low. These results suggested that the deep seawater was useful for the prevention of hyperlipidemia and arteriosclerosis compared to the surface seawater, and it was found that reduction of the LDL cholesterol level and enhancement of GPx activity were involved in its effects.

Pharmacological activity of deep-sea water: examination of hyperlipemia prevention and medical treatment effect.

When normal rabbits were administered various samples of deep-sea water, their biochemical values changed within normal limits, and no differences from distilled water administration (control) group levels were observed. Furthermore, no histopathological changes were observed in internal organs on the 28th day after administration. The serum total cholesterol (T-Cho) and low density lipoprotein cholesterol (LDL-Cho) levels of normal rabbits fed with a 1% cholesterol-containing diet simultaneously administered deep-sea water (desalinated water, hardness 28, 300, and 1200) increased with time up to about 1500 mg/dl. However, the degrees of increase were smaller than those of the control group, which received distilled water. Furthermore, when prepared hyperlipemia rabbits were administered deep-sea water (desalinated water, hardness 28, 300, and 1200), there were no significant changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), high density lipoprotein cholesterol (HDL-Cho), or triglyceride (TG) levels. On the other hand, T-Cho and LDL-Cho levels were reduced when the rabbits were changed to normal food, and the degree of reduction was more than that of the control group. In the liver and main artery bow, as the hardness of the deep-sea water increased, the accumulation of lipid and permeation of macrophages was reduced. This result was well in agreement with the results of the T-Cho and LDL-Cho levels. From these results, it is clear that deep-sea water controls the increase of serum lipid values (T-Cho and LDL-Cho) of cholesterol-fed rabbits, and promotes the reduction of serum lipid hyperlipemia rabbits. The minerals in deep-sea water greatly influence this effect.

Relationship between the eosinophilia of bronchoalveolar lavage fluid (BALF) and the severity of pulmonary fibrosis induced by bleomycin in rats.

A large number of studies have demonstrated that the presence of eosinophils in the lungs of patients with pulmonary fibrosis correlates with poor prognosis or resistance to therapy. However, direct evidence of the relationship between the influx of eosinophil and pulmonary fibrosis has not yet been described experimentally. In this article, pulmonary fibrosis was induced by different doses of bleomycin (BLM) and using different aged rats. On selected days afterwards, the lungs were lavaged and harvested for analyzing fibrosis, eosinophil influx and cytokine expression. There was a significant relationship between eosinophilia and the pulmonary fibrosis (r=0.98, p<0.01). In spite of the fact that there was no significant increase in hydroxyproline of the lung, eosinophil influxes of bronchoalveolar lavage fluid (BALF) was maximal 7 d after BLM administration. Moreover, there were similar patterns among transforming growth factor beta (TGF)-beta(1), hepatocyte growth factor (HGF) and eosinophil influx of BALF in that they were dependent on dose of BLM and age. These findings, taken together, have suggested the causal correlation of eosinophilia during the early stage with subsequent pulmonary fibrosis. The possible role of eosinophils in the pathogenesis of pulmonary fibrosis might contribute to not only TGF-beta(1) but also HGF production.