Experimental and computational studies of sulfided NiMo supported on pillared clay: catalyst activation and guaiacol adsorption sites.

We report on intermediate (oxysulfides) and sulfided structures of NiMo supported on aluminium pillared clay (Al-PILC) during the catalyst activation process and the prefered guaiacol adsorption sites on the sulfided catalyst. In situ X-ray absorption fine structure (XAFS) together with density functional theory (DFT) calculations confirm the existence of ill-defined suboxides (MoOx, NiOx) and the well-known subsulfides (Mo2S9, Ni3S2) at the first stage which, at a later stage in the process, transform into MoS2 with two edges, oxygen-decorated Mo and Ni with zero sulfur coverage. The freshly sulfided NiMoS2 catalyst under sulfiding agents is mainly terminated by Mo-edge surface with 50% sulfur coverage (Mo-S50) with a disordered Ni-edge surface that can be assigned as NiMoS (1̄010). When exposed to an inert atmosphere such as He gas, the Mo and Ni edges evolved partially into new structures of Mo and Ni edges with zero sulfur coverage, labelled as Mo-Bare and Ni-Bare. Guaiacol is often used as a model compound for lignin and a series of calculations of guaiacol on the structural edges of a sulfided NiMoS2 catalyst show relatively good agreement between the observed and calculated inelastic neutron scattering (INS) spectra for Mo-S50, Ni-Bare, and NiMoS (1̄010) where guaiacol weakly chemisorbed via oxygen atom of OH group. The results also confirm that guaiacol is physisorbed on the basal plane of NiMoS2 in a horizontal (flat-lying) configuration via van der Waals interaction at a separation of about 3.25 Å.

Older adults with history of falls are unable to perform walking and prehension movements simultaneously.

Older adults have a greater incidence of falls, and risk of falls will increase when combining two motor tasks. Thus, it is interesting to investigate the effect of fall history on motor performance in older adults when combining walking with another task such as grasping an object. The aim of this study was to investigate the combined task of walking and prehension with different levels of manual task difficulty in older adults with and without a history of falls. Thirty older adults participated in this study; groups were designated as fallers (n=15) and non-fallers (n=15). Participants were asked to reach-to-grasp a dowel during quiet standing and during walking. Level of manual task difficulty was manipulated by the type of dowel support and obstacles located at different distances to the sides of the dowel. Fall history influenced the performance of this combined task for the most difficult manual conditions. Fallers were able to be identified due to differences in the grasping strategies used while walking compared to non-fallers. In addition, walking and grasping were mutually modulated due to the level of difficulty of the manual task.

[Indications and controindications of hormone replacement therapy in menopause]. / Indicazioni e controindicazioni della terapia ormonale sostitutiva in menopausa

Menopause is a physiological event of women's life that is the end of menstrual cycles and the end of the fertile period. Normally the age at which women reach menopause is between 50 and 52 years, as the world average. Menopause occurs when the functional ovarian reserve is exhausted or can be induced by surgical removal of the ovaries. What follows, however, is the establishment of a state of hypoestrogenism, which potentially affects various organs and systems (genito-urinary system, cardiovascular system, skeleton, skin, brain) and quality of life of women (varying degrees of vasomotor symptoms, vaginal atrophy, osteoporosis). Hormone replacement therapy (HRT), it is based on estrogen or estrogen and progesterone, can be used to compensate for estrogen deficiency and to prevent or limit the damages that may result. During the years, there have been several observational studies designed to identify the risks and benefits arising from the use of postmenopausal hormone replacement therapy, in spontaneous and surgical menopause. In fact, although several studies have shown that women treated with estrogen enjoyed a better overall level of health, over the last decade have raised doubts about the safety of hormone replacement therapy long term. In our study we try to discuss, based on a review of the literature and evidence available to date, what are the present indications and controindications to the use of hormone replacement therapy.

Perfusional evaluation of postesophagectomy gastroplasty with a radioisotopic study.

SUMMARY: Anastomotic fistula represents one of the frequent causes of postoperative morbidity and mortality following transhiatal esophageal resections. The main etiological factor is the ischemia of the gastric tube created for digestive transit reconstruction. Evidence suggests that per operative hypoperfusion can be maintained or even impaired after the surgery. Several methods have been employed in an attempt to assess the blood perfusion of the gastric flap, but they all pose limitations. However, there is a chronological relationship between perfusion assessments, which are almost exclusively performed per operatively, and the occurrence of a leak, which commonly appears several days after the surgery. The authors have developed a method of gastric perfusion evaluation by single photon emission computed tomography scintigraphy, which corrects that temporal matter, allowing the estimation of postoperative gastric perfusion. It is noninvasive, low cost, and may be applied by the time frame when most fistulas occur. High correlation between the event fistula and the low radiotracer uptake in the group of studied patients could be demonstrated. A role in the research of perfusion evaluation of different types of esophageal reconstruction is suggested.

Serial regulation of transcriptional regulators in the yeast cell cycle.

Genome-wide location analysis was used to determine how the yeast cell cycle gene expression program is regulated by each of the nine known cell cycle transcriptional activators. We found that cell cycle transcriptional activators that function during one stage of the cell cycle regulate transcriptional activators that function during the next stage. This serial regulation of transcriptional activators forms a connected regulatory network that is itself a cycle. Our results also reveal how the nine transcriptional regulators coordinately regulate global gene expression and diverse stage-specific functions to produce a continuous cycle of cellular events. This information forms the foundation for a complete map of the transcriptional regulatory network that controls the cell cycle.

Loss of collagen type IV in rheumatoid synovia and cytokine effect on the collagen type-IV gene expression in fibroblast-like synoviocytes from rheumatoid arthritis.

Collagen type IV is a structural matrix protein which contributes to the structural organization of the synovia. In order to characterize the distribution of this protein in synovia with chronic synovitis, collagen type IV was detected by immunochemistry in normal synovia and in synovia from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). A decrease of collagen type IV was observed in synovial layers of rheumatoid synovia, which statistically correlated with the grade of inflammation and with the thickness of the synovial layer. In vitro, we found no differences in the gene expression of collagen type IV in cultures of fibroblast-like synoviocytes (FLS) derived from OA and RA using a reverse-transcriptase polymerase chain reaction. Nevertheless, we observed a downregulating effect of tumor necrosis factor-alpha and interleukin (IL)-1beta on the gene expression of collagen type IV only in FLS isolated from patients with RA. The effect of IL-1beta was dose dependent. In summary, we observed an inflammation-associated decrease of collagen type IV in the synovial layer of rheumatoid synovia. Inflammatory cytokines may play a role in regulating the synthesis of collagen type IV in the rheumatoid process in vivo.

Seltene Manifestation einer Grossgefassvaskulitis bei|| systemischem Lupus erythematodes.

Case-reports from two female patients with an occlusion||| of the right external iliac artery and femoral artery are presented due to a||| large-vessel vasculitis. Both patients suffered from systemic lupus||| erythematosus This rare manifestation occurred within the first few years of||| the disease and was important for prognosis and further treatment. Other||| manifestations of the disease were general symptoms and polyarthritis. In one||| case the vasculitis was confirmed by histology. A fibrous thickening of the||| intima and a vasculitis of small vessels within the adventitia were the||| prominent feature. This observation supports the idea of small vessel||| vasculitis as the characteristic manifestation in lupus||| erythematosus.

[Rare manifestation of large vessel vasculitis in systemic lupus erythematosus]. / Seltene Manifestation einer Grossgefässvaskulitis bei systemischem Lupus erythematodes.

Case-reports from two female patients with an occlusion of the right external iliac artery and femoral artery are presented due to a large-vessel vasculitis. Both patients suffered from systemic lupus erythematosus This rare manifestation occurred within the first few years of the disease and was important for prognosis and further treatment. Other manifestations of the disease were general symptoms and polyarthritis. In one case the vasculitis was confirmed by histology. A fibrous thickening of the intima and a vasculitis of small vessels within the adventitia were the prominent feature. This observation supports the idea of small vessel vasculitis as the characteristic manifestation in lupus erythematosus.

[Molecular mechanisms of cell-cell and cell-matrix interactions in the pathophysiology of rheumatoid arthritis]. / Molekulare Mechanismen der Zell-Zell- und Zell-Matrix-Interaktionen in der Pathophysiologie der Rheumatoiden Arthritis.

The original structure of the synovial membrane is completely destroyed in the rheumatoid synovium and is characterized by mononuclear cell infiltration, synoviocyte proliferation, neo-vascularization, and deposition of extracellular matrix proteins. Adhesion molecules play an important role in the development of these pathologic changes. In this review we discuss the role of the adhesion receptors of the selectin, integrin and immunoglobulin families and of the CD44 molecule in the cell-cell and cell-matrix interaction in the pathogenesis of the inflammatory changes in rheumatoid arthritis.

Loss of laminin and of the laminin receptor integrin subunit alpha 6 in situ correlates with cytokine induced down regulation of alpha 6 on fibroblast-like synoviocytes from rheumatoid arthritis.

OBJECTIVE: To investigate in situ the expression of the integrin receptor subunits alpha 6 and beta 1 and the distribution of the ligand laminin in the synovia from osteoarthritis (OA) and rheumatoid arthritis (RA) patients and to study the effect of cytokines and antirheumatic drugs on the expression of the alpha 6 and beta 1 integrin subunits on long term cultures of fibroblast-like synoviocytes (FBS) derived from OA and RA. METHODS: The expression of the alpha 6 and beta 1 integrin subunits and the distribution of laminin were examined immunohistochemically in normal synovia and in synovia from patients with OA and RA. The effect of proinflammatory cytokines (IL1 beta and TNF alpha), and of antirheumatic drugs (salicylic acid, dexamethasone, and methotrexate) on the alpha 6 and beta 1 expression of cultured normal FBS and FBS from patients with OA and RA was determined by flow cytometry. RESULTS: In normal synovia and in OA synovia samples with a low grade of inflammation, synovial lining cells (SLC) showed a parallel expression and distribution of alpha 6 and laminin. In synovia samples of OA with a higher grade of inflammation and in the majority of RA synovia samples laminin was pericellularly distributed in a low number of SLC, whereas alpha 6 was expressed on the surface of a high number of SLC. In RA synovia samples with severe inflammatory changes the gradual loss of laminin generally corresponded to a decrease of the alpha 6 integrin subunit. beta 1 was always strongly expressed in all synovia samples detected. Proinflammatory cytokines up regulated the expression of alpha 6 and beta 1 on OA-FBS, whereas these effectors decreases alpha 6 and beta 1 on RA-FBS. In contrast, antirheumatic drugs, in particular methotrexate and dexamethasone, reduced the expression of alpha 6 and beta 1 on OA-FBS, whereas the same treatment on RA-FBS stimulated the expression of these integrin subunits. CONCLUSION: The gradual loss of laminin in chronic synovitis may contribute to the altered expression of alpha 6 in SLC. IL1 beta and TNF alpha down regulated the expression of the alpha 6 and beta 1 integrin subunits on long term cultures of FBS derived from RA. Therefore, these cytokines may be among the effectors regulating the expression of the alpha 6 integrin subunit in SLC in vivo. As antirheumatic drugs increase the expression of alpha 6 on RA-FBS, the presence of the laminin receptor may confer a protective effect on the synovia in vivo.

Pleural mesothelioma mimics the integrin profile of activated, sessile rather than detached mesothelial cells.

Mesothelial cells (MC) form a polarized monolayer lining serosal cavities. During serositis, the MC lining undergoes hyperplasia, and MC are shed into effusions. During these processes, contact with basement membrane and, ultimately, neighboring cells is at least temporarily lost, suggesting regulated alterations in cell/matrix and cell/cell adhesion. Such interactions are primarily mediated by integrins. Malignant mesothelioma has a growth pattern characterized by lateral, limited invasive but contiguous spread. During serositis, activated MC, both sessile and detached, expressed an extended spectrum of beta1, beta3 and beta4 integrins compared with resting MC, as shown by immunohistology. Malignant mesothelioma had an integrin repertoire and a subcellular distribution resembling that of activated sessile rather than floating MC. In vitro, MC exposed a more comprehensive pattern of integrins than that of the newly established mesothelioma cell lines ME-HD-1 and ME-HD-2, as shown by flow cytometry. MC consistently adhered better than mesothelioma cells to laminin, tenascin, fibronectin and collagen type IV. Adhesion of MC and mesothelioma cells to these matrix proteins was, at least in part, mediated via beta1 integrins. The different integrin profiles and adhesion properties of cultured MC and mesothelioma cells may reflect a limited functional differentiation of the latter.

Methotrexate in patients with moderate systemic lupus erythematosus (exclusion of renal and central nervous system disease).

OBJECTIVES: Methotrexate (MTX) has been used in several autoimmune diseases. Apart from its use in rheumatoid arthritis, MTX has been assessed in small studies in patients with vasculitis, uveitis, and inflammatory bowel disease. The aim of this study was to evaluate the efficacy of MTX in a particular group of patients with systemic lupus erythematosus (SLE). PATIENTS: In an open prospective study 22 patients fulfilling the ACR criteria for SLE were included. Patients had one or more of the following manifestations; active non-destructive polyarthritis, dermatitis, vasculitis of the skin, pleuritis. All patients had been treated with corticosteroids for at least six months without achieving remission. Sixteen patients were taking antimalarial drugs in addition to corticosteroids, which were stopped at the beginning of the trial. Patients with renal and central nervous involvement were excluded from the study. All patients received MTX orally at a dose of 15 mg/week over six months. Corticosteroids were continued. As additional medication only indomethacin up to 100 mg/day was permitted if used before the start of the study. The outcome was evaluated using the SLE disease activity index (SLEDAI). RESULTS: Disease activity was evaluated after six months of MTX treatment. All patients completed the study period. The SLEDAI decreased significantly from mean (SD) 12.2 (3.99) to 4 (3.75) (p = 0.001). The prednisolone dose was reduced from a mean (SD) of 17.4 (12.8) at the beginning to 8.8 (5.36) mg/day at the end point of the study (p = 0.01). MTX was well tolerated. Four patients complained of general malaise. Two patients had transient increases in liver enzymes. In no case did MTX have to be stopped. CONCLUSIONS: In an open prospective study methotrexate was used in SLE patients with particular clinical characteristics. MTX was shown to be effective in reducing disease activity and sparing the dose of corticosteroids. Further controlled studies are necessary.

Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins.

OBJECTIVE: To compare in vitro expression of beta 1, beta 3, and beta 4 integrins in normal fibroblast-like synoviocytes (FBS) and in FBS from rheumatoid arthritis (RA) synovium and to investigate the adhesion of normal FBS and RA-FBS to the integrin binding extracellular matrix (ECM) proteins: collagen type IV, fibronectin, laminin, and tenascin. METHODS: Expression of integrin receptors of cultured FBS was detected by flow cytometry. Attachment of FBS to ECM proteins was quantified by adhesion assays. Inhibition studies were performed using monoclonal antibodies to the integrin subunits. RESULTS: Compared with normal FBS, RA-FBS showed increased expression of alpha 1 to alpha 6, beta 1, and beta 4 integrin subunits and enhanced binding of ECM proteins. Binding to ECM proteins was partly or completely blocked by an anti-beta 1 integrin antibody and antibodies to alpha 3, alpha 5, and alpha 6 integrin subunits. The blocking efficiency was significantly (P < 0.05) higher in RA-FBS than in normal FBS. CONCLUSIONS: The enhanced expression of the beta 1 integrin receptors on cultured RA-FBS correlated with increased attachment to ECM proteins. Adhesion of normal and RA-FBS to ECM proteins is mediated through beta 1 integrin receptors. Therefore, the tight binding of rheumatoid FBS to the matrix via beta 1 integrins might play a role in ECM remodelling in the rheumatoid process in vivo.

Differential expression and functional behaviour of the alpha v and beta 3 integrin subunits in cytokine stimulated fibroblast-like cells derived from synovial tissue of rheumatoid arthritis and osteoarthritis in vitro.

OBJECTIVE: The aim of this study was to investigate in situ the expression of the classic vitronectin (VN) receptor consisting of the alpha v and beta 3 subunits in synovial lining cells (SLC) of chronic synovitis occurring in osteoarthritis (OA) and in rheumatoid arthritis (RA). The expression and function of alpha v and beta 3 as VN receptor in cultured fibroblast-like synoviocytes (FBS) derived from patients with OA and RA was also compared. METHODS: Expression of alpha v and beta 3 was examined immunohistochemically in normal synovial tissue and in synovial tissue from patients with OA and RA. The effect of proinflammatory cytokines and of a synovial fluid of a patient with RA on the expression of the alpha v and beta 3 subunits of cultured FBS was determined by flow cytometry. Binding of OA and RA-FBS to VN was quantified using adhesion assays and the effect of interleukin 1 beta (IL1 beta) and tumour necrosis factor alpha (TNF alpha) on adhesion was measured. The specificity of the adhesion was tested by inhibition studies using monoclonal antibodies to integrin subunits. RESULTS: In in situ studies normal SLC showed a parallel distribution of alpha v and beta 3 subunits. OA-SLC strongly and uniformly expressed alpha v whereas RA-SLC showed heterogeneous expression of alpha v. In situ both OA-SLC and RA-SLC lacked the expression of the integrin subunit beta 3. In in vitro studies, OA-FBS and RA-FBS did not differ as regards expression of alpha v and beta 3, and VN attachment. Binding of RA-FBS to VN was partially blocked by antibodies against alpha v, beta 1, and beta 3 subunits, whereas only antibodies against alpha v and beta 3 inhibited the binding of OA-FBS to VN. The proinflammatory cytokines TNF alpha and IL1 beta increased the expression of alpha v and beta 3, and the VN binding of OA-FBS, whereas alpha v and beta 3 expression, and VN binding were downregulated in RA-FBS. Similar effects were found when the synovial fluid of an RA patient was used. CONCLUSION: The integrin subunit beta 3 seems to be one partner but not the major one with which the subunit alpha v forms functional vitronectin receptors in OA-FBS and RA-FBS. The interaction between synovial cells and inflammatory cytokines seems to be different for OA and RA; the basis for this difference, however, remains to be established.

Pharmacological evidence for tumor necrosis factor as a mediator of allergic inflammation in the airways.

Tumor necrosis factor (TNF) has been implicated in the pathophysiology of a number of inflammatory diseases of the lung. Using the TNF receptor fusion protein, Ro 45-2081, our study investigated the involvement of TNF in allergic inflammatory responses in the airways of sensitized guinea pigs and Brown-Norway rats. Sensitized guinea pigs exhibited an enhanced airway reactivity to substance P (1-10 micrograms/kg, i.v.) at 6 hr after antigen challenge which was inhibited (P < .05) by Ro 45-2081 (3 mg/kg, i.p.). Treatment with Ro 45-2081 (1-3 mg/kg, i.p.) dose-dependently inhibited (P < .05) the accumulation of neutrophils and total cells in bronchoalveolar lavage fluid in sensitized guinea pigs examined at 6 and 24 hr postchallenge. Ro 45-2081 (3 mg/kg, i.p.) also significantly (P < .05) reduced the number of eosinophils in bronchoalveolar lavage at both time points whereas a lower dose (1 mg/kg, i.p.) had no effect. Ro 45-2081 (1 or 3 mg/kg, i.p.) abolished antigen-induced microvascular leakage (quantified by tissue content of Evans blue dye) in the trachea and main bronchi in sensitized guinea pigs. In the Brown-Norway rat, Ro 45-2081 (1-3 mg/kg, i.p.) caused a dose-dependent inhibition of neutrophil and eosinophil infiltration into bronchoalveolar lavage fluid at 24 hr after antigen challenge. In both guinea pig and Brown-Norway rat models, treatment with dexamethasone (30 mg/kg, i.p., for guinea pig and 0.3 mg/kg, i.p., for Brown-Norway rat) produced virtually identical results to those obtained with Ro 45-2081. The ability of Ro 45-2081 to inhibit antigen-induced responses in sensitized animals suggests that TNF is a mediator of allergic inflammation in the lung.

Comparison of cyclic and linear analogs of vasoactive intestinal peptide.

A series of i-->i + 4 side-chain to side-chain lactam analogs of vasoactive intestinal peptide has been prepared in order to study the effect of cyclization on biological activity. In vitro, on guinea pig tracheal smooth muscle and on human bronchial tissue, approximately half of the cyclic analogs showed increased potency and half were decreased over the linear analogs. Several cyclic compounds were between 10- and 20-fold more potent and one was 290-fold more potent than the linear species. In vivo, in guinea pigs, the cyclic compounds showed increased potency by up to 70-fold and significantly enhanced duration of action as compared to linear compounds.

Structure-activity studies on the vasoactive intestinal peptide pharmacophore. 1. Analogs of tyrosine.

From previous work, the primary functional groups, i.e. side chains, of the vasoactive intestinal peptide which are responsible for interaction with the VIP receptor have been identified. One of these sites, the side chain of tyrosine22 is essential for high receptor affinity. The present work aims to examine this site in greater detail. Several Boc-substituted-phenylalanine derivatives were prepared and incorporated into VIP analogs as replacement for tyrosine22. These analogs, of the form Ac-[Lys12,Nle17,X22,Val26,Thr28]-VIP, were assayed as smooth muscle relaxants and found to be full agonists of native VIP. Most of the analogs, however, proved to be less potent than the parent analog by up to 300-fold. A few analogs, all possessing electron-donating substituents, retained nearly full potency. Two compounds, 3-F,4-OH-Phe, 42 and 3-OCH3,4-OH-Phe, 43, were found to be 1.5- and 3.4-fold more potent than the parent compound, which equates to being 8.9- and 20-fold more potent than native VIP. Compound 43 was also found to be active as a bronchodilator in vivo in guinea pigs, with slightly over 2-fold enhanced potency and a significantly longer duration of action (> 20 min) when compared to the parent compound (5 min). The physical characteristics of the various substituents and their effect on biological activity are discussed with a brief analysis by QSAR techniques.

[Normal synoviocytes and synoviocytes from osteoarthritis and rheumatoid arthritis bind extracellular matrix proteins differently]. / Normale Synoviozyten und Synoviozyten aus Osteoarthritis und rheumatoider Arthritis binden unterschiedlich an extrazelluläre Matrixproteine.

Extracellular matrix proteins are increased in inflammatory synovitis. We showed previously that the in situ expression of the corresponding extracellular matrix receptors (beta 1-integrins) is enhanced in synoviocytes (SC) of synovitis of different etiology (16). To investigate the adhesion of SC to extracellular matrix proteins, we examined the attachment of SC from normal and inflamed synovia to fibronectin, tenascin, laminin and collagen type IV. Compared to normal SC and SC of osteoarthritis, SC of rheumatoid arthritis showed an increased binding to tenascin, laminin, fibronectin and collagen type IV, suggesting a distinctive interaction of SC and extracellular matrix proteins in rheumatoid arthritis. Furthermore, the increased binding of SC of rheumatoid arthritis to extracellular matrix proteins may play a role in tissue remodelling associated with rheumatoid arthritis.

[The significance of cardiolipin antibodies in systemic lupus erythematosus]. / Die Bedeutung von Cardiolipinantikörpern beim systemischen Lupus erythematodes.

The aim of the study was to investigate the frequency and clinical significance of anticardiolipin antibodies (aCL) in systemic lupus erythematosus (SLE). 32 of 100 patients with SLE had positive anticardiolipin antibodies. Increased aCL were associated with thrombosis, thrombocytopenia, miscarriage, vasculitic skin changes and neurological symptoms. The incidence of thrombosis, thrombocytopenia, and neurological symptoms was significantly increased in the aCL-positive group as compared to the aCL-negative group. These findings confirm the results of former investigations and underline the role of aCL in systemic lupus erythematosus.

Ro 25-1553: a novel, long-acting vasoactive intestinal peptide agonist. Part II: Effect on in vitro and in vivo models of pulmonary anaphylaxis.

Studies were conducted to compare the effect of native vasoactive intestinal peptide (VIP), Ro 25-1553 (a cyclic peptide analog of VIP) and salbutamol (a beta2-adrenoceptor agonist) on antigen-induced pathophysiological effects in the guinea pig. Ro 25-1553 and salbutamol (0.01-1.0 microM) prevented antigen-induced contractions of the guinea pig trachea in vitro with IC50 values of 0.07 and 0.05 microM, respectively. VIP (0.01-1.0 microM) had no effect on antigen-induced tracheal contractions. Aerosolized Ro 25-1553 and salbutamol were equipotent in preventing antigen-induced increases in guinea pig lung resistance (IC50 value = 0.0001%), whereas aerosolized VIP (0.1%) was ineffective. Ro 25-1553 (0.1-100 micrograms), instilled intratracheally 2 min before the antigen challenge of buffer-perfused lungs from sensitized guinea pigs, produced a dose-dependent inhibition of bronchoconstrictor, vasoconstrictor and edemagenic responses, whereas intratracheal VIP (100 micrograms) had no effect. Intratracheal salbutamol (0.1-100 micrograms) inhibited antigen-induced responses in a manner comparable to Ro 25-1553. Lung inflammation was assessed as leukocyte accumulation in bronchoalveolar lavage fluid after the antigen provocation. Aerosolized antigen-induced bronchoalveolar lavage eosinophilia (13-fold increase over saline controls) at 6 hr after challenge was prevented in a concentration-dependent manner by pretreatment with nebulized Ro 25-1553 and salbutamol, but not by pretreatment with native VIP. These results indicate that Ro 25-1553 suppresses various pathophysiological features associated with pulmonary anaphylaxis and asthma, including airway reactivity, edema formation and granulocyte accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)