Tobacco smoke exposure and multiplexed immunoglobulin E sensitization in children: a population-based study.

BACKGROUND: Although there is evidence that exposure to tobacco smoke is harmful to children's respiratory health, the effects of tobacco smoke exposure on the regulation of immunoglobulin E (IgE)-mediated immune responses to specific allergens remain unclear. This study aimed to investigate the relationship between objectively assessed tobacco smoke exposure and specific IgE profiles for a broad spectrum of allergens in a population setting. METHODS: Children aged 5-18 years (N = 1315) were assessed using serum cotinine measurement and microarray-based multiplexed detection of specific IgE against 40 allergens. RESULTS: Serum cotinine levels were positively associated with sensitization to foods (adjusted odds ratio [AOR] = 4.95; 95% CI: 1.59-15.34), cockroaches (AOR = 3.77; 95% CI: 1.49-9.51), and pollen (AOR = 2.84; 95% CI: 1.20-6.73) while the association was borderline significant for animals (AOR = 2.53; 95% CI: 0.92-6.93). No associations were found for sensitization against mites, mold, and latex. When considering the degree of allergic sensitization, serum cotinine levels were positively correlated to the number of sensitization to cockroaches (P = 0.004), pollen (P = 0.006), and foods (P < 0.001), with statistically significant positive dose-response relationships (all P < 0.01). Similar results were observed when summing up specific IgE concentrations for the aforementioned allergen categories. CONCLUSIONS: The association between tobacco smoke exposure and IgE sensitization to environmental allergens varies for different allergens among children. This study demonstrates that elevated serum cotinine levels are significantly associated with IgE sensitization to cockroaches, grass pollen, and certain foods, with potential dose-dependent relationships.

Rejection of cardiac xenografts transplanted from alpha1,3-galactosyltransferase gene-knockout (GalT-KO) pigs to baboons.

The use of alpha1,3-galactosyltransferase gene-knockout (GalT-KO) swine donors in discordant xenotransplantation has extended the survival of cardiac xenografts in baboons following transplantation. Eight baboons received heterotopic cardiac xenografts from GalT-KO swine and were treated with a chronic immunosuppressive regimen. The pathologic features of acute humoral xenograft rejection (AHXR), acute cellular xenograft rejection (ACXR) and chronic rejection were assessed in the grafts. No hyperacute rejection developed and one graft survived up to 6 months after transplantation. However, all GalT-KO heart grafts underwent graft failure with AHXR, ACXR and/or chronic rejection. AHXR was characterized by interstitial hemorrhage and multiple thrombi in vessels of various sizes. ACXR was characterized by TUNEL(+) graft cell injury with the infiltration of T cells (including CD3 and TIA-1(+) cytotoxic T cells), CD4(+) cells, CD8(+) cells, macrophages and a small number of B and NK cells. Chronic xenograft vasculopathy, a manifestation of chronic rejection, was characterized by arterial intimal thickening with TUNEL(+) dead cells, antibody and complement deposition, and/or cytotoxic T-cell infiltration. In conclusion, despite the absence of the Gal epitope, acute and chronic antibody and cell-mediated rejection developed in grafts, maintained by chronic immunosupression, presumably due to de novo responses to non-Gal antigens.

Human leukocyte antigen-DR matching improved skin graft survival from transgenic pigs to accommodate SCID mice reconstituted with human peripheral blood mononuclear cells.

The shortage of human organs has encouraged scientists to develop genetically modified pigs for xenotransplantation, such as CD55 or CD46, and CD59 transgenesis as well as alpha-galactosyl transferase gene knockouts. In allotransplantation, the match of human leukocyte antigen class II (HLA-II) may improve graft survival although the role of HLA-II in xenotransplantation is unknown. HLA-II transgenic pigs, including DP, DQ, and DR, have been successfully generated and HLA-DR15+ transgenic pig skin pieces grafted onto severe congenital immunodeficiency (SCID) mice reconstituted intraperitoneally with HLA-DR15+ or HLA-DR15(-) human peripheral blood mononuclear cells (hPBMCs). This study sought to develop an animal model to evaluate the effects of HLA-DR matching on xenograft survival. Human CD4+ and CD8+ were detected from days 7 to 29 after hPBMC reconstitution in SCID mice. Both CD4+ and CD8+ cells of HLA-DR15(-) reconstituted SCID mice were significantly higher at day 29 postgrafting compared with HLA-DR15+ reconstituted SCID mice. An HLA-DR15+ transgenic pig dermal graft survived and integrated into SCID mice reconstituted with hPBMCs/HLA-DR15+ as proven by the histopathological finding that the collagen layer remained intact with little lymphocytic response. In contrast, the transgenic pig dermal graft showed more collagen disruption as well as mild to moderate lymphocytic infiltration when reconstituted in an hPBMC/HLA-DR15(-) SCID mouse. The results suggested that HLA-DR matching eased xenograft rejection; however, it was not yet clear that the response was mediated by T cells.

Long-term survival of HLA-DR15+ pig skin in SCID mice after reconstitution with human peripheral blood mononuclear cells and under short-term immunosuppression.

In allotransplantation, donor-recipient human leukocyte antigen (HLA) matches improve graft survival. For studies of the role of donor-recipient HLA II matching on xenotransplantation, we successfully generated HLA-DR15+ transgenic pigs the the skins of which were transplanted to SCID mice, which were thereafter reconstituted with HLA-DR15+ or -DR15(-) hPBMC. Cyclosporine was given intraperitoneally to SCID mice for 12 days. Human T cells were observed in SCID mice after reconstitution. Mixed lymphocytes responses showed greater responses by HLA-DR15(-) human peripheral blood mononuclear cells (hPBMC) against HLA-DR15+ porcine PBMC. HLA-DR15+ porcine skins survived more than 100 days in all SCID mice. HLA-DR15+ porcine skins were rejected in all non-SCID (Balb/c) mice. The histologic pictures of transplanted HLA-DR15+ porcine skins showed surviving porcine epithelium in remodeling murine dermis and little lymphocyte infiltration into the murine dermis. The long-term survival of HLA-DR15+ pig skin in all hPBMC-SCID mice might be due to poor engraftment or function of reconstituted T cells. Further studies are needed to clarify the role of donor-recipient matching of HLA-DR15.

Detection and quantification of glucuro- and sulfoconjugated metabolites in human urine following oral administration of xenobiotic 19-norsteroids.

Recently, the endogenous origin of nandrolone (19-nortestosterone) and other 19-norsteroids has been a focus of research in the field of drug testing in sport. In the present study, we investigated metabolites conjugated to a glucuronic acid and to a sulfuric acid in urine following administration of four xenobiotic 19-norsteroids. Adult male volunteers administered a single oral dose (10 mg) of each of four 19-norsteroids. Urinary samples collected from 0 to 120 h were subjected to methanolysis and beta-glucuronidase hydrolysis and were derivatized by N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) before gas chromatography-mass spectrometry analysis. We confirmed that 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE) were present in both glucuronide (g) and sulfate (s) conjugates and 19-norepiandrosterone (19-NEA) was excreted exclusively as a sulfate fraction in urine of all 19-norsteroids tested. The overall levels of the three metabolites can be ranked as follows: 19-NA(g+s)>19-NE(g+s)>19-NEA(s). The concentration profiles of these three metabolites in urine peaked between 2 to 12h post-administration and declined thereafter until approximately 72-96 h. 19-NA was most prominent throughout the first 24 h post-administration, except for a case in which an inverse relationship was found after 6h post-administration of nandrolone. Furthermore, we found that sulfate conjugates were present in both 19-NA and 19-NE metabolites in urine of all 19-norsteroids tested. The averaged total amounts of metabolites (i.e. 19-NA(s+g)+19-NE(s+g)+19-NEA(s)) excreted in urine were 38.6, 42.9, 48.3 and 21.6% for nandrolone, 19-nor-4-androsten-3,17-dione, 19-nor-4-androsten-3beta,17beta-diol and 19-nor-5-androstene-3beta,17beta-diol, respectively. Results from the excretion studies demonstrate significance of sulfate-conjugated metabolites on interpretation of misuse of the 19-norsteroids.

Troponin T levels in baboons with pig heterotopic heart transplants.

Troponin T levels have been monitored in baboons (n = 8) undergoing pig heterotopic heart transplantation, and correlated with a decrease in graft contractions and graft survival. Pig heart graft survival was from 12 to 139 days (mean 45, median 33), and graft failure was associated with predominant thrombotic microangiopathy and ischemia, with focal hemorrhage, and edema. An increase in troponin T levels 5 to 6 days before graft failure correlated closely with diminished graft contractions. An increase in troponin T was a reliable indicator that graft dysfunction was occurring.

Direct comparison of liposomal doxorubicin with or without polyethylene glycol coating in C-26 tumor-bearing mice: is surface coating with polyethylene glycol beneficial?

Sterically stabilized liposome is characterized by a surface coating of polyethylene glycol (PEG) or other polymers that can reduce opsonization of the liposome by plasma proteins. It has a higher plasma area under the concentration-time curve (AUC), which is believed to correlate with better therapeutic efficacy. However, the presence of large molecules on the liposomal surface may reduce the interactions of liposomes with cells and hinder entry of liposomes into the tumor tissue. Using a stable liposomal system composed of distearoyl phosphatidylcholine/cholesterol, we examined the effect of PEG (Mr 2000) on the pharmacokinetics and on the efficacy of liposomal doxorubicin with C-26 syngeneic tumor model in BALB/c mice. The plasma AUC of liposomal doxorubicin with 6 mol-% PEG-modified distearoyl phosphatidylethanolamine (PEG-DSPE) was approximately twice that of liposomal doxorubicin without PEG at various dosages, regardless of whether the mice were tumor-bearing. Paradoxically, the group of mice treated with liposomal doxorubicin without PEG had higher tumor doxorubicin concentrations. The 72-h tumor AUC was 1.44 times that of liposomal doxorubicin with 6% PEG-DSPE. The tumor-accumulation efficiency (AUC(Tumor)/AUC(Plasma)) of liposomal doxorubicin without PEG was 0.87, and this was more than twice that of the liposomal doxorubicin with 6% PEG-DSPE (0.31). At a dose of 10 mg/kg, although both liposomal groups were better than the free drug group in terms of clinically relevant parameters, including toxicity, tumor shrinkage, and survival, there was no difference between the two liposomal drug groups. In this stable liposome system, surface coating with PEG offered no benefit for liposomal doxorubicin in the C-26 tumor model. To enhance the therapeutic index of liposomal doxorubicin, simply increasing plasma AUC by surface coating with PEG may not be satisfactory.

Potential of aspirin to inhibit thrombotic microangiopathy in alpha1,3-galactosyltransferase gene-knockout pig hearts after transplantation in baboons.

Hearts from alpha1,3-Galactosyltransferase gene-knockout (GaIT-KO) pigs were transplanted heterotopically into 8 baboons that received an anti-CD154 monoclonal antibody (mAb)-based immunosuppressive regimen and heparin. Three baboons died or were euthanized with beating grafts on 16, 23, and 56 days, respectively, and the remaining 5 grafts functioned for 59-179 days. Hyperacute rejection did not occur, and classical features of acute humoral xenograft or acute cellular rejection were rare. However, thrombotic microangiopathy (TM) developed in all cases; its onset was delayed in 2 baboons that received aspirin. Function of a pig organ in a baboon for a period approaching 6 months has not been reported previously and lends encouragement that the barriers to xenotransplantation will be overcome, but TM requires investigation.

Thyrotropin modulates receptor-mediated processing of the atrial natriuretic peptide receptor in cultured thyroid cells.

In a prior study of atrial natriuretic peptide (ANP) binding to cultured thyroid cells, we reported that at 4 C, more than 95% of bound ANP is recovered on cell membranes, with negligible ANP internalization observed. Since ANP binding was inhibited by TSH, we have further studied TSH effects on postbinding ANP processing to determine whether this phenomenon reflects enhanced endocytosis of the ANP-receptor complex. An ANP chase study was initiated by binding [125I] ANP to thyroid cells at 4 C for 2 h, followed by incubation at 37 C. ANP processing was then traced by following 125I activity at various time intervals in three fractions: cell surface membranes, incubation medium, and inside the cells. Radioactivity released into medium represented processed ANP rather than ANP dissociated from surface membranes, since prebound [125I]ANP could not be competitively dissociated by a high concentration of ANP (1 mumol/L) at 37 C. Chase study results showed that prebound ANP quickly disappeared from cell membranes down to 34% by 30 min. Internalized ANP peaked at 10 min, with 21% of initial prebound ANP found inside the cells. At the same time, radioactivity recovered in incubation medium sharply increased between 10-30 min from 8% to 52%. Preincubation of cells with chloroquine (which blocks degradation of the ANP-receptor complex by inhibiting lysosomal hydrolase) caused a 146% increase in internalized [125I]ANP by 30 min (39% compared to 15% control), while medium radioactivity decreased from 52% to 16%, suggesting that processing of the receptor complex is mediated via lysosomal enzymes. In chase studies employing cells pretreated with chloroquine, TSH stimulated the internalization rate of ANP-receptor complex. By 30 min, TSH significantly reduced the membrane-bound ANP, and the decrease was inversely correlated to the increase in internalized radioactivity. In the absence of ANP ligand, TSH also modulated receptor translocation, resulting in decreased receptor number on surface membrane. However, TSH did not affect ANP degradation on the basis of analysis by immunoprecipitation and high performance liquid chromatography. Taken together, these data suggest that TSH downregulates ANP receptor on thyroid cell surface membranes, and that an ANP degradative pathway exists which is not mediated through receptor binding.

Alloantibody and xenoantibody cross-reactivity in transplantation.

The recent availability of pigs homozygous for alpha1,3-galactosyltransferase gene knockout, and improved immunosuppressive regimens that prevent an elicited antibody response, are expected to contribute to significantly increased survival of pig organs transplanted into primates, bringing clinical trials of xenotransplantation closer. Patients highly sensitized to human leukocyte antigens, who may be precluded from obtaining a human donor organ, would be one group that might benefit from xenotransplantation. However, there have been few studies on whether there is cross-reactivity of anti-human leukocyte antigen antibodies with pig antigens. What data there are suggest that such cross-reactivity exists and that this may be detrimental to the outcome after transplantation of a pig organ. Neither is it known whether sensitization after a pig xenograft would preclude subsequent allotransplantation, although the data available suggest that this will not be the case. Further investigation on allo- and xenoantibody cross-reactivity is required.

Transneuronal WGA-HRP: can it demonstrate development of ocular dominance patches and effects of monocular deprivation?

We have attempted to use intraocular injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) to label ocular dominance patches in developing layer 4 of cat visual cortex. The cortices of animals killed at 49 days or later showed normal ocular dominance patches similar to those seen in [3H]proline material. Animals killed at 42 days showed some patches, but also showed unsegregated regions. Animals killed younger were difficult to stain and did not have patches. We also examined the ability of the WGA-HRP technique to demonstrate the effects of monocular deprivation (MD). MD for the first 3 months of life produced expansion of the afferents from the nondeprived eye and retraction of the patches from the deprived eye. One week of MD at about 5 weeks of age produced an expansion of the patches innervated by the nondeprived eye, but did not obviously affect the patches innervated by the deprived eye. We conclude that WGA-HRP is useful for examining the effects of long-term MD on ocular dominance patches but not for following the development of segregation. Its advantages over the [3H]proline technique are that it does not require a delay of many weeks before the sections can be examined and is much less expensive.

Redoing reconstruction of the esophagus using remnants of the ileo-left colon aided by microvascular anastomosis.

Theoretically, the jejunum, fasciocutaneous or myocutaneous flap is recommended as an esophageal substitute in redoing reconstruction of the esophagus after a second incidence of corrosive injury. However, other esophageal substitutes should also be considered. We present a case of a 42-year-old woman who underwent esophageal reconstruction using an ileocolon graft for corrosive esophageal stricture ten years before. The patient ingested caustic drain cleaner again and underwent resection of the ileocolon graft secondary to corrosive necrosis. Two and a half months after the second incidence of corrosive injury, reconstruction of the esophagus was again performed using a graft of remnant ileo-left colon aided by microvascular anastomosis. The patient was able to swallow a regular diet after the procedure. Remnant ileo-left colon is a good alternative esophageal substitute in cases of repeated corrosive injury.

Immunohistochemical analysis of epidermal growth factor receptor family members in stage I non-small cell lung cancer.

BACKGROUND: To elucidate the relationship between the expression of epidermal growth factor receptor family members (ErbB-1, neu/ErbB-2, ErbB-3, and ErbB-4) and tumor recurrence. METHODS: We used immunohistochemistry to examine the expression of four epidermal growth factor receptor family members in 73 patients with stage I non-small cell lung cancer. RESULTS: Using Cox univariate analysis, we determined that angiolymphatic tumor emboli and non-well-differentiated tumor cells were two significant conventional pathologic predictors of tumor recurrence, and that ErbB-1 and ErbB-3 were also significant predictors. Co-expression of ErbB-1+, -3+, or expression of three or more epidermal growth factor receptor family members had a significant effect on lung cancer recurrence. A stepwise multivariate Cox proportional hazards regression analysis provided a predictive model for tumor recurrence. CONCLUSIONS: The present study shows that in patients with a non-well-differentiated tumor, overexpression of ErbB-3 is a useful marker for predicting tumor recurrence. The present study also confirmed that ErbB-1 expression increased in proportion to the loss of tumor differentiation. The correlation between ErbB-3 and distant metastasis was good.

Origins of sympathetic innervation to the mesenteric vein vessel in cats.

Physiological and histochemical studies have clearly demonstrated the control and innervation of the sympathetic nerve on the splanchnic veins. However, the origins of postganglionic fibers remain to be determined. In this study, we used the retrograde transport of horseradish peroxidase (HRP) technique to trace the origins of postganglionic neurons in pre- and paravertebral sympathetic ganglia that innervate the mesenteric vein. A segment (6-8 mm) of mesenteric vein close to the duodeno-jejunal junction was isolated. HRP was applied externally on the vein segment to allow uptake into the nerve endings. In 10 cats, there was a total of 9275 HRP-labeled neurons in the pre- and paravertebral ganglia. The neuron distribution (mean +/- S.E.M.) was as follows: 452 +/- 77 (49%) in the superior mesenteric ganglion (SMG), 248 +/- 62 (27%) in the right celiac ganglion (RCG), 111 +/- 23 (12%) in the left celiac ganglion (LCG) and 58 +/- 16 (6%) in the splanchnic ganglia. Although the appearance of HRP neurons in the paravertebral ganglia (T10-L3) was relatively sparse, there were still significant numbers in L1 (26 +/- 13, 3%), T13 (15 +/- 5, 2%) and other ganglia. The results indicate that more than 90% of the presynaptic sympathetic neurons innervating the mesenteric vein make their synaptic connections in the prevertebral ganglia, mostly SMG and then RCG as well as LCG. Postsynaptic neurons arising directly from the paravertebral ganglia (mostly L1 and T13) constitute to about 6% of the total.

Intrathoracic muscle flap transposition in the treatment of fibrocavernous tuberculosis.

BACKGROUND AND OBJECTIVE: Conventionally, pulmonary resection with thoracoplasty is used to treat fibrocavernous complication of pulmonary tuberculosis. This operation is usually bloody, time-consuming with complicated postoperative course. To prevent massive blood loss and preserved pulmonary function, a more simplified operative procedure, cavernostomy combined intrathoracic muscle flap transposition was used and the outcome was evaluated in this study. DESIGN: Retrospective review. METHODOLOGY: Between December 1989 and June 1996, a total of ten patients with fibrocavernous pulmonary tuberculosis were managed using cavernostomy combined with intrathoracic muscle flap transposition. Five of them had concomitant aspergilloma within the cavity while three had multiple drug resistant pulmonary tuberculosis. The muscle flap was used to plombage the cavity and reinforce the closure of bronchopleural fistula after cavernostomy. RESULTS: Six postoperative complications occurred in five patients, including reformation of cavity (2), bronchopleurocutaneous fistulae (3), and postoperative bleeding (1). The success or failure of intrathoracic muscle flap transposition on patients with fibrocavernous tuberculosis was significantly correlated with the size of the cavity (194.0+/-11.2 vs. 283.0+/-44.6 cm(3), P=0.016) and the number of bronchopleural fistulae (1.6+/-0.4 vs. 4.0+/-0.4, P=0.008). There was no operative death and in long term follow-up, there was no recurrence of hemoptysis or deterioration of pulmonary function in the successful group of patients. CONCLUSIONS: Cavernostomy combined with intrathoracic muscle flap transposition can be used to treat well-selected fibrocavernous pulmonary tuberculosis patients, except on patients with large size cavity, multiple bronchopleural fistulae or multiple drug resistance tuberculosis.

Iodothyronines: oxidative deiodination by hemoglobin and inhibition of lipid peroxidation.

Purified rat hemoglobin catalyzes the oxidative degradation of iodothyronines to form iodide and an iodine-containing intermediate that reacts with protein. Hemoglobin also catalyzes peroxidation of linoleic acid. These observations are consistent with the reported intrinsic peroxidase activity of hemoglobin and other heme-proteins. However, incubations containing both linoleic acid and an iodothyronine produced a surprising result: deiodination was stimulated rather than competitively inhibited. In contrast, linoleic-acid peroxidation was inhibited by iodothyronines. Thus, low levels of iodothyronines (2.6 X 10(-7) M) are effective inhibitors of linoleic-acid peroxidation. Thyroxine and reverse T3 were found to be more effective in this antioxidant activity than vitamin E, glutathione, ascorbic acid and DTT. Since linoleic-acid peroxidation proceeds by a propagating free-radical mechanism, we have concluded that iodothyronines can effectively terminate the free-radical chain reaction to become oxidatively deiodinated. Consistent with this antioxidant mechanism, reverse T3 is effective in preserving red cell membranes as measured by the inhibition of erythrocyte hemolysis.

Surgery for lung abscess in immunocompetent and immunocompromised children.

PURPOSE: The aim of this study was to evaluate the surgical management results of lung abscess in immunocompetent and immunocompromised children. METHODS: Surgery was performed on 30 children with lung abscess or necrotizing pneumonia refractory to medical treatment in a 12-year period. Of them, 23 were immunocompetent, and 7 were immunocompromised. Pulmonary resection was performed including unilateral lung in 28, bilateral in 2, and 2 lobes in 6. Concomitant decortication was performed in 18 (78.2%) immunocompetent patients. RESULTS: Increased incidence of surgery for lung abscess was caused mainly by drug-resistant and fungal infection. Surgery was performed commonly for bacterial lung abscess on patients less than 5 years old and fungal lung abscess on adolescence. A multiple small abscess was the predominant type of abscess in immunocompetent patients, whereas 2-lobe involvement tended to occur in immunocompromised patients. Fungal lung abscess tended to occur on left lung and in female patients. Left lower lobe was involved most commonly in both groups of patients in which majority need lobectomy. Immunocompromised patients required a more extensive pulmonary resection. There were 3 postoperative complications (morbidity of 10.2%) with no postoperative mortality. Length of postoperative hospital stay ranged from 6 to 85 days with average of 18.4 days. CONCLUSIONS: The incidence and pattern of lung abscess that required surgery between immunocompetent and immunocompromised children were different. A more aggressive, extensive surgical procedure is preferable for immunocompromised patients, and the surgical results were comparatively excellent to immunocompetent patients. However, the prognosis of immunocompromised children depends on their underlying disease process.

Giant intraluminal fibrovascular polyp of the esophagus.

Giant polyps of the esophagus are relatively rare. Without previous history, the diagnosis of the disease is difficult to be made by esophagography and esophagoscopy. A case of giant intraluminal fibrovascular polyp (13x4x3.5 cm) of the esophagus is presented. The polyp was retrieved from the esophagus by a Foley's catheter and resected via the oral route.

Lightning injury: report of a case.

Lightning injury can cause severe damage to many systems and often results in a high mortality. We report a case of sustained lightning injury in which a 54-year-old woman presented with heart failure, pulmonary edema and consciousness disturbance. The patient was found unconscious, lying face down on the ground of a trash dump on the day of a thunderstorm. No deformities were seen in the extremities, but scattered third degree burns (less than 1%) were found on her neck where her necklace had been. Ventilator and inotropic agents with an adequate fluid supply were used. A Swan-Ganz catheter was inserted for monitoring. The patient was discharged two weeks later with an uneventful clinical course, except for mild neurologic sequelae (amnesia, disorientation).

Improvements in endotoxemic syndromes using a disintegrin, rhodostomin, through integrin αvß3-dependent pathway.

BACKGROUND AND OBJECTIVES: Septic shock is a major cause of morbidity and mortality in intensive care units, but there is still no effective therapy for the patients. We evaluated the effects of rhodostomin (Rn), an Arg-Gly-Asp-containing snake venom disintegrin, on lipopolysaccharide (LPS)-activated phagocytes in vitro and LPS-induced endotoxemia in vivo. METHODS AND RESULTS: Rn inhibited adhesion, migration, cytokine production and mitogen-activated protein kinase (MAPK) activation of macrophage induced by LPS. Flow cytometric analysis revealed that Rn specifically blocked anti-αv mAb binding to RAW264.7. Besides inhibiting MAPK activation of THP-1, Rn bound to LPS-activated THP-1 and specifically blocked anti-αvß3 mAb binding to THP-1. Binding assays proved that integrin αvß3 was the binding site for rhodostomin on phagocytes. Rn reversed the enhancement of fibronectin and vitronectin on LPS-induced monocyte adhesion and cytokine release. Transfection of integrin αv siRNA also inhibited LPS-induced activation of monocyte, and Rn exerted no further inhibitory effect. Furthermore, Rn significantly decreased the production of tumor necrosis factor-α (TNF-a), interleukin (IL)-6, -1ß and -10 and attenuated cardiovascular dysfunction, including blood pressure and heart pulse, and thrombocytopenia in LPS-induced endotoxemic mice. Rn also protected against tissue inflammation as evidenced by histological examination. CONCLUSIONS: Rn may interact with αvß3 integrin of monocytes/macrophages leading to interfere with the activation of phagocytes triggered by LPS. These results suggest that the protective function of Rn in LPS-induced endotoxemia may be attributed to its anti-inflammation activities in vivo.