Perforation of the Small Intestine after Introduction of Lenvatinib in a Patient with Advanced Hepatocellular Carcinoma.

Lenvatinib is a first-line standard treatment for advanced hepatocellular carcinoma (HCC) with better anti-tumor effects than sorafenib, as shown by greater inhibition of the kinases of fibroblast growth factor receptor and vascular endothelial growth factor (VEGF) receptor. This report describes a patient with advanced HCC who experienced perforation of the small intestine 1 month after starting the treatment with lenvatinib. This patient likely had partial necrosis of a metastasis to the small intestine before starting lenvatinib treatment, with subsequent ischemic changes leading to perforation of the small intestine. Although metastasis of HCC to the small intestine is rare, patients with these metastases should be regarded as being at risk for perforation during lenvatinib treatment.

Novel treatment for chronic pododermatitis in an Indian elephant (Elephas maximus indicus) with Mohs' paste.

Asian and African elephants are frequently afflicted by foot disorders that can be very challenging to manage even with aggressive therapy. Such conditions may have indirect life-threatening effects. Mohs' paste (zinc chloride based escharotic agent) was used to treat a female Indian elephant (Elephas maximus indicus) aged 39 years with foot disorder at Kanazawa Zoological Gardens. Degenerated hyperplastic tissue was observed inside the hoofs of digits 2 and 5. Mohs' paste was applied on the lesions, which coagulated the hyperplastic tissue and restrained its proliferation. Subsequently, the hyperplastic tissue could be trimmed with little pain, and the disorder became manageable. Mohs' paste treatment was effective and is expected to be an alternative treatment for hoof disorder.

Direct observation of Mn and Ni ordering in LiMn1.5Ni0.5O4 using atomic resolution scanning transmission electron microscopy.

LiMn1.5Ni0.5O4 is an excellent candidate as a cathode-active material in high-voltage lithium-ion batteries and studied using atomic resolution scanning transmission electron microscope. High-angle annular dark-field (HAADF) images obtained at [100] orientation demonstrate that Mn and Ni atoms are regularly ordered at octahedral sites in a spinel structure, in a 3:1 ratio between columns with high and low intensities. Simulations of HAADF images revealed that atomic columns including Mn exhibit a larger intensity than that by Ni columns, primarily because of the effect of the Debye-Waller factor.

Rapamycin attenuates pulmonary allergic vasculitis in murine model by reducing TGF-ß production in the lung.

BACKGROUND: Rapamycin has been reported to inhibit mesenchymal cell proliferation in a murine model of pulmonary fibrosis. In the present study, we examined the effects of rapamycin on vascular remodeling including intraluminal myofibroblast proliferation in a murine model of allergic vasculitis with eosinophil infiltration. METHODS: C57BL/6 mice were sensitized with ovalbumin (OVA) and alum. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice was administered with rapamycin (1mg/kg) intraperitoneally, in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and concentrations of IL-4, IL-5, IL-13 and TGF-ß in the BAL fluid (BALF) were measured. Semi-quantitative analysis of pathological changes in the pulmonary arteries was evaluated according to the severity of vasculitis. RESULTS: The number of eosinophils in BALF was reduced significantly in the mice treated with rapamycin compared to the positive control. There was a significant decrease in the TGF-ß concentration of the BALF in the rapamycin-treated group compared to that of the positive control. The pathological scores were reduced significantly in the rapamycin-treated group compared to the positive control group. Intraluminal myofibroblasts in pulmonary arteries were reduced dramatically in the rapamycin-treated group compared to the positive control group. CONCLUSIONS: Rapamycin suppressed pulmonary vascular remodeling in a murine model of allergic vasculitis with eosinophil infiltration through reducing eosinophil infiltration and TGF-ß production in the lung and inhibition against biological action of TGF-ß.

Scedosporium aurantiacum brain abscess after near-drowning in a survivor of a tsunami in Japan.

Many victims of the tsunami that occurred following the Great East Japan Earthquake on March 11, 2011 developed systemic disorders owing to aspiration pneumonia. Herein, we report a case of tsunami lung wherein Scedosporium aurantiacum was detected in the respiratory tract. A magnetic resonance image of the patient's head confirmed multiple brain abscesses and lateral right ventricle enlargement. In this case report, we describe a potential refractory multidrug-resistant infection following a tsunami disaster.

Effects of imatinib mesylate on pulmonary allergic vasculitis in a murine model.

OBJECTIVES: Imatinib mesylate (IM) is a potent and specific tyrosine inhibitor and has been reported to inhibit mesenchymal cell proliferation in pulmonary fibrosis. In the present study, we examine the effects of IM on vascular remodeling in a murine model of allergic vasculitis with eosinophil infiltration. METHODS: C57BL/6 mice were sensitized with ovalbumin (OVA) and alum. The positive controls were exposed to aerosolized OVA daily for 7 days. IM treated mice with exposure to OVA were administered IM in parallel with daily exposure to aerosolized OVA for 7 days. On the 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and the concentrations of cytokines in the BAL fluid (BALF) were measured. Semi-quantitative analysis of pathological changes in the pulmonary arteries was evaluated according to the criteria of severity of vasculitis. Immunohistochemistry for Ki-67 to detect proliferating cells was performed. RESULTS: The number of eosinophils in BALF was reduced significantly in the IM-treated group compared to the positive control. There was no significant difference in the concentrations of interleukin (IL)-2, IL-4, IL-5, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, tumor growth factor (TGF)-ß or platelet-derived growth factor in the BAL fluid between the positive control and the IM-treated group. The pathological scores of vasculitis and the ratio of Ki-67-positive intra-luminal cells were reduced significantly in the IM-treated group compared to the control group after OVA exposure. CONCLUSION: IM-suppressed pulmonary vascular remodeling in a murine model of allergic vasculitis with eosinophil infiltration.

Association of IL-13 gene polymorphisms with airway hyperresponsiveness in a Japanese adult asthmatic population.

BACKGROUND: A single nucleotide polymorphism (SNP; rs20541) in the IL-13 gene has been recognized as a risk factor for asthma. This SNP causes Arg to Gln (Q) substitution at position 110 in the mature IL-13 protein. We have recently showed that FEV1 in asthmatics with the Q110 variant of IL-13 declined faster, and progressive airway remodeling was observed in these subjects (Wynn, 2003 [1]). However, the effects of the IL-13 variant on airway hyperresponsiveness (AHR) remain to be elucidated. We analyzed the relationship between SNP rs20541 in IL-13 and AHR in asthmatics. METHODS: We recruited 182 asthmatics who visited the asthma outpatient clinic at Iwate Medical University Hospital from 2006 to 2011. Subjects were genotyped for rs20541. Asthma severity, atopic status, age of asthma onset, serum IgE concentration, AHR, and pulmonary function were studied in these subjects. AHR was measured using the continuous methacholine inhalation method (Astograph; Chest; Tokyo, Japan). RESULTS: Genotyping of rs20541 revealed 26 A/A, 77 A/G, and 79 G/G patient genotypes. The D min (U) of the 3 genotypes was 1.17±0.300 in A/A, 1.99±0.35 in A/G, and 2.85±0.39 in G/G. The D min in the 3 genotypes was significantly different. Spirometric data revealed that % FEV1 and % FEF75 were significantly different among the 3 groups of IL-13 genotypes, whereas no significant differences were observed in therapeutic steps, atopic status, house dust mite sensitization, or serum IgE concentration. CONCLUSION: The SNP rs20541 in IL-13 was associated with AHR in Japanese adult asthmatics.

Anti-breast cancer potential of daidzein in rodents.

AIMS: This study was carried out to explore anti-breast cancer potential of isoflavone daidzein or its related compounds using appropriate animal models and their anti-tumor mechanism. MAIN METHODS: Daidzein or its major metabolite equol at a dose molar equivalent to tamoxifen [1.0 mg(2.7 µmol)/kg or 10 mg (27 µmol)/kg/day] was treated orally to rats bearing 7,12-dimethylbenz(a)anthracene(DMBA)-induced mammary tumors or ovariectomized athymic nude mice implanted with human MCF-7 breast cancer xenograft and an estrogen pellet. The growth of tumors was monitored for several weeks after the treatment. The cell-cycle and apoptotic stages in mammary tumors collected from rats were analyzed by flow cytometry. Immunohistochemistry analysis was also used to determine the expression of caspase-3. KEY FINDINGS: Oral treatment with daidzein or equol at a human equivalent dose suppressed the growth of both DMBA-induced mammary tumors and human MCF-7 breast cancer xenografts in rodents, the inhibitory activity being superior to that of genistein or tamoxifen. Strong apoptosis induced by daidzein or equol contributes to the anti-tumor potential. SIGNIFICANCE: Daidzein and its metabolite equol showed the potential of inhibiting the growth of mammary tumors in rodents. Daidzein or equol could be used as a core structure to design new drugs for breast cancer therapy. Our results indicate that consumption of daidzein may protect against breast cancer.

Multiple Scedosporium apiospermum abscesses in a woman survivor of a tsunami in northeastern Japan: a case report.

INTRODUCTION: Scedosporium apiospermum is increasingly recognized as a cause of localized and disseminated mycotic infections in near-drowning victims. CASE PRESENTATION: We report the case of a 59-year-old Japanese woman who was a survivor of a tsunami in northeastern Japan and who had lung and brain abscesses caused by S. apiospermum. Initially, an aspergillus infection was suspected, so she was treated with micafungin. However, computed tomography scans of her chest revealed lung abscesses, and magnetic resonance images demonstrated multiple abscesses in her brain. S. apiospermum was cultured from her bronchoalveolar lavage fluid, and antimycotic therapy with voriconazole was initiated. Since she developed an increase in the frequency of premature ventricular contractions, an adverse drug reaction to the voriconazole was suspected. She was started on a treatment of a combination of low-dose voriconazole and liposomal amphotericin B. After combination therapy, further computed tomography scans of the chest and magnetic resonance images of her brain showed a demarcation of abscesses. CONCLUSIONS: Voriconazole appeared to have a successful record in treating scedosporiosis after a near drowning but, owing to several adverse effects, may possibly not be recommended. Thus, a combination treatment of low-dose voriconazole and liposomal amphotericin B may be a safe and effective treatment for an S. apiospermum infection. Even though a diagnosis of scedosporiosis may be difficult, a fast and correct etiological diagnosis could improve the patient's chance of recovery in any case.

Competence-dependent endogenous DNA rearrangement and uptake of extracellular DNA give a natural variant of Streptococcus mutans without biofilm formation.

The production of water-insoluble glucan (WIG) enables Streptococcus mutans to survive and persist in the oral niche. WIG is produced from sucrose by glucosyltransferase encoded tandemly by the highly homologous gtfB and gtfC genes. Conversely, a single hybrid gene from the endogenous recombination of gtfB and gtfC is easily generated using RecA, resulting in S. mutans UA159 WIG- (rate of ∼1.0×10(-3)). The pneumococcus recA gene is regulated as a late competence gene. comX gene mutations did not lead to the appearance of WIG- cells. The biofilm collected from the flow cell had more WIG- cells than among the planktonic cells. Among the planktonic cells, WIG- cells appeared after 16 h and increased ∼10-fold after 32 h of cultivation, suggesting an increase in planktonic WIG- cells after longer culture. The strain may be derived from the biofilm environment. In coculture with donor WIG+ and recipient WIG- cells, the recipient cells reverted to WIG+ and acquired an intact gtfBC region from the environment, indicating that the uptake of extracellular DNA resulted in the phenotypic change. Here we demonstrate that endogenous DNA rearrangement and uptake of extracellular DNA generate WIG- cells and that both are induced by the same signal transducer, the com system. Our findings may help in understanding how S. mutans can adapt to the oral environment and may explain the evolution of S. mutans.

Anti-breast cancer potential of SS5020, a novel benzopyran antiestrogen.

Treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. The carcinogenic effect is thought to involve initiation and/or promotion resulting from DNA damage induced by TAM as well as its estrogenic action. To minimize this serious side-effect while increasing the anti-breast cancer potential, a new benzopyran antiestrogen, 2E-3-{4-[(7-hydroxy-2-oxo-3-phenyl-2H-chromen-4-yl)-methyl]-phenyl}-acrylic acid (SS5020), was synthesized. Unlike TAM, SS5020 exhibits no genotoxic activity to damage DNA. Furthermore, SS5020 does not present significant uterotrophic potential in rats; in contrast, the structurally related compounds, TAM, toremifene, raloxifene (RAL) and SP500263 all have uterotrophic activity. At the human equivalent molar dose of TAM (0.33 or 1.0 mg/kg), SS5020 had much stronger antitumor potential than those same antiestrogens against 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. The growth of human MCF-7 breast cancer xenograft implanted into athymic nude mice was also effectively suppressed by SS5020. SS5020, lacking genotoxic and estrogenic actions, could be a safer and stronger antiestrogen alternative to TAM and RAL for breast cancer therapy and prevention.

Quantitative detection of 4-hydroxyequilenin-DNA adducts in mammalian cells using an immunoassay with a novel monoclonal antibody.

Estrogen-DNA adducts are potential biomarkers for assessing the risk and development of estrogen-associated cancers. 4-Hydroxyequilenin (4-OHEN) and 4-hydroxyequilin (4-OHEQ), the metabolites of equine estrogens present in common hormone replacement therapy (HRT) formulations, are capable of producing bulky 4-OHEN-DNA adducts. Although the formation of 4-OHEN-DNA adducts has been reported, their quantitative detection in mammalian cells has not been done. To quantify such DNA adducts, we generated a novel monoclonal antibody (4OHEN-1) specific for 4-OHEN-DNA adducts. The primary epitope recognized is one type of stereoisomers of 4-OHEN-dA adducts and of 4-OHEN-dC adducts in DNA. An immunoassay with 4OHEN-1 revealed a linear dose-response between known amounts of 4-OHEN-DNA adducts and the antibody binding to those adducts, with a detection limit of approximately five adducts/10(8) bases in 1 microg DNA sample. In human breast cancer cells, the quantitative immunoassay revealed that 4-OHEN produces five times more 4-OHEN-DNA adducts than does 4-OHEQ. Moreover, in a mouse model for HRT, oral administration of Premarin increased the levels of 4-OHEN-DNA adducts in various tissues, including the uterus and ovaries, in a time-dependent manner. Thus, we succeeded in establishing a novel immunoassay for quantitative detection of 4-OHEN-DNA adducts in mammalian cells.

Equine estrogen-induced mammary tumors in rats.

Long-term hormone replacement therapy is associated with an increased risk of breast, ovarian and endometrial cancers in women. Equine estrogens are a principal component of hormone replacement therapy; however, their tumorigenic potential toward mammary tissue and reproductive organs has not been extensively explored. A pellet containing equilin was inserted under the skin of female ACI rats and the development of mammary tumors was monitored. Histological examination revealed premalignant lesions such as apocrine metaplasia in whole-mount preparations of mammary gland from the equilin-treated rats. ACI rats given 10mg equilin developed palpable mammary tumors at 13 weeks of treatment, and 37.5% of the rats developed mammary tumors within 15 weeks. For 2.5mg equilin, palpable tumors were observed in 8.3% of the rats after 8 weeks' treatment; the frequency was lower than that (42.9%) observed with 2.5mg E(2). No tumors were observed in the untreated rats. Evidently, equilin is a mammary carcinogen, and this potential may be associated with development of breast and reproductive cancers in women receiving hormone replacement therapy.

Anti-breast cancer potential of SS1020, a novel antiestrogen lacking estrogenic and genotoxic actions.

Long-term treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. Several antiestrogens developed in last decades have been discontinued from clinical testing because of their undesirable effects on the uterus. To avoid such serious side-effect while increasing the drug's anti-breast cancer potential, new triphenylethylene antiestrogens, 2E-3-{4-[(E)-4-chloro-1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]-phenyl} acrylic acid (SS1020) and 2E-3-{4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenyl}acrylic acid (SS1010), were designed as safer alternatives. Unlike TAM, SS1020 does not present significant uterotrophic potential in rats; in contrast, SS1010, a compound removing a 4-OH moiety from SS1020, represented weak uterotrophic activity. The structurally related compounds 4-hydroxytamoxifen, toremifene, ospemifene, raloxifene (RAL) and GW5638 all have uterotrophic activity. In addition, SS1020 and SS1010 exhibit no genotoxic activity to damage hepatic DNA in rats. Therefore, SS1020 was selected as a safer antiestrogen candidate and used for evaluating the antitumor potential in animals. At the human equivalent doses of TAM, SS1020 had antitumor potential much higher than that of TAM, RAL and GW5638 against 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. The growth of human MCF-7 breast cancer xenograft implanted into athymic nude mice was also effectively suppressed by SS1020. SS1020, lacking estrogenic and genotoxic actions and having strong antitumor potency superior to that of TAM and RAL, could be a safer alternative for breast cancer therapy and prevention.

Detoxification of aristolochic acid I by O-demethylation: less nephrotoxicity and genotoxicity of aristolochic acid Ia in rodents.

Ingestion of aristolochic acids (AA) contained in herbal remedies results in aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA I and AA II, primary components in AA, have similar genotoxic potential, whereas only AA I shows severe renal toxicity in rodents. AA I is demethylated to form 8-hydroxy-aristolochic acid I (AA Ia) as a major metabolite. However, the nephrotoxicity and genotoxicity of AA Ia has not yet been determined. AA Ia was isolated from urine collected from rats treated with AA I and characterized by NMR and mass spectrometry. The purified AA Ia was administered intraperitoneally to C3H/He male mice for 9 days and its toxicity was compared with AA I. Using (32)P-postlabeling/polyacrylamide gel electrophoresis, the level of AA Ia-derived DNA adducts in renal cortex was approximately 70-110 times lower than that observed with AA I, indicating that AA Ia has only a limited genotoxicity. Supporting this result, when calf thymus DNA was reacted with AA Ia in a buffer containing zinc dust, the formation of AA Ia-DNA adducts was two-orders of magnitude lower than that of AA I. Histopathologic analysis revealed that unlike AA I, no significant changes were detected in the renal cortex of mice treated with AA Ia. Therefore, the contribution of AA Ia to renal toxicity is minimum. We conclude the metabolic pathway of converting AA I to AA Ia functions as the detoxification of AA I.

Cytogenetic abnormality 46,XX,add(21)(q11.2) in a patient with follicular dendritic cell sarcoma.

The case of a patient with follicular dendritic cell (FDC) sarcoma with chromosomal aberration add(21)(q11.2) is described. Cytogenetic studies showed the karyotype 46,XX,add(21)(q11.2)[3]/46,XX[17], although the encoded protein involved was not clarified. The abnormal pattern was quite simple, and different from a previous report. The clinical course of the FDC sarcoma in this case has been indolent, as for most FDC sarcoma patients. Although this patient suffered from breast carcinoma 6 years after the onset of FDC sarcoma, the carcinoma showed different histological and phenotypic profiles.

Miscoding properties of 6alpha- and 6beta-diastereoisomers of the N(2)-(estradiol-6-yl)-2'-deoxyguanosine DNA adduct by Y-family human DNA polymerases.

Treatment with estrogen increases the risk of breast, ovary, and endometrial cancers in women. DNA damage induced by estrogen is thought to be involved in estrogen carcinogenesis. In fact, Y-family human DNA polymerases (pol) eta and kappa, which are highly expressed in the reproductive organs, miscode model estrogen-derived DNA adducts during DNA synthesis. Since the estrogen-DNA adducts are a mixture of 6alpha- and 6beta-diastereoisomers of dG-N(2)-6-estrogen or dA-N(6)-6-estrogen, the stereochemistry of each isomeric adduct on translesion synthesis catalyzed by DNA pols has not been investigated. We have recently established a phosphoramidite chemical procedure to insert 6alpha- or 6beta-isomeric N(2)-(estradiol-6-yl)-2'-deoxyguanosine (dG-N(2)-6-E(2)) into oligodeoxynucleotides. Using such site-specific modified oligomer as a template, the specificity and frequency of miscoding by dG-N(2)-6alpha-E(2) or dG-N(2)-6beta-E(2) were explored using pol eta and a truncated form of pol kappa (pol kappaDeltaC). Translesion synthesis catalyzed by pol eta bypassed both the 6alpha- and 6beta-isomers of dG-N(2)-6-E(2), with a weak blockage at the adduct site, while translesion synthesis catalyzed by pol kappaDeltaC readily bypassed both isomeric adducts. Quantitative analysis of base substitutions and deletions occurring at the adduct site showed that pol kappaDeltaC was more efficient than pol eta by incorporating dCMP opposite both 6alpha- and 6beta-isomeric dG-N(2)-6-E(2) adducts. The miscoding events occurred more frequently with pol eta, but not with pol kappaDeltaC. Pol eta promoted incorporation of dAMP and dTMP at both the 6alpha- and 6beta-isomeric adducts, generating G --> T transversions and G --> A transitions. One- and two-base deletions were also formed. The 6alpha-isomeric adduct promoted slightly lower frequency of dCMP incorporation and higher frequency of dTMP incorporation and one-base deletions, compared with the 6beta-isomeric adduct. These observations were supported by steady-state kinetic studies. Taken together, the miscoding property of the 6alpha-isomeric dG-N(2)-6-E(2) is likely to be similar to that of the 6beta-isomeric adduct.

Oxidative DNA damage in XPC-knockout and its wild mice treated with equine estrogen.

Long-term hormone replacement therapy with equine estrogens is associated with a higher risk of breast, ovarian, and endometrial cancers. Reactive oxygen species generated through redox cycling of equine estrogen metabolites may damage cellular DNA. Such oxidative stress may be linked to the development of cancers in reproductive organs. Xeroderma pigmentosa complementation group C-knockout ( Xpc-KO) and wild-type mice were treated with equilenin (EN), and the formation of 7,8-dihydro-8-oxodeoxyguanosine (8-oxodG) was determined as a marker of typical oxidative DNA damage, using liquid chromatography electrospray tandem mass spectrometry. The level of hepatic 8-oxodG in wild-type mice treated with EN (5 or 50 mg/kg/day) was significantly increased by approximately 220% after 1 week, as compared with mice treated with vehicle. In the uterus also, the level of 8-oxodG was significantly increased by more than 150% after 2 weeks. Similar results were observed with Xpc-KO mice, indicating that Xpc does not significantly contribute to the repair of oxidative damage. Oxidative DNA damage generated by equine estrogens may be involved in equine estrogen carcinogenesis.

Increased antitumor potential of the raloxifene prodrug, raloxifene diphosphate.

Raloxifene (RAL) significantly reduced the incidence of breast cancer in women at high risk of developing the disease. Unlike tamoxifen (TAM), an increased incidence of endometrial cancer was not observed in women treated with RAL. However, RAL, having two hydroxyl moieties, can be conjugated rapidly through phase II metabolism and excreted, making it difficult to achieve adequate bioavailability by oral administration in humans. As a result, higher doses must be administered to obtain an efficacy equivalent to that achieved with TAM. To improve oral bioavailability and antitumor potential, RAL diphosphate was prepared as a prodrug. RAL diphosphate showed several orders of magnitude lower binding potential to both ER alpha and ER beta and weak antiproliferative potency on cultured human MCF-7 and ZR-75-1 breast cancer cells, as compared to RAL. However, RAL diphosphate has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL against both 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats and human MCF-7 breast cancer implanted in athymic nude mice. The RAL prodrug may provide greater clinical benefit for breast cancer therapy and prevention.

Effects of theophylline on chronic inflammatory lung injury induced by LPS exposure in guinea pigs.

BACKGROUND: Pathogenesis of COPD is, at least in part, attributable to the chronic accumulation of neutrophils in the airways, and morphological changes such as hyperplasia of goblet cells in the airways are often observed in this disease. These structural changes were induced in guinea pigs by repetitive inhalations of LPS, and the effects of theophylline and dexamethasone were examined. METHODS: Male Hartley Guinea pigs weighing about 300 g were exposed to a nebulized solution of LPS (30 microg/mL) for 1 hour. Exposure to LPS was performed 15 times at 48-hour intervals. Histological analysis was performed, and infiltration of leukocytes in BALF, airway hyperreactivity and hydroxyproline content of the lung were measured 24 or 48 hours after the final exposure of LPS. Drugs were administered every day until 30 minutes before the final exposure. RESULTS: Repetitive exposure to LPS induced an influx of inflammatory cells into the BALF. Histological changes such as accumulation of inflammatory cells in the lung parenchyma, enlargement of alveoli, swelling of the alveolar walls and goblet cell hyperplasia in the airways were observed. Airway hyperreactivity and increased lung hydroxyproline content were also found in this model of chronic inflammatory lung injury. Some of these changes induced by repetitive LPS exposure were improved by treatment with theophylline or dexamethasone. CONCLUSIONS: Theophylline improved airway injury as well as airway hyperreactivity induced by repetitive exposure of the guinea pigs to LPS. These results suggest that theophylline treatment has ameliorative effects on airway disease with chronic inflammation.