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Biomedical subjects

M S Mulligan

Publications and source records attributed to M S Mulligan.

At least 37 records · Page 2Linked to original sources
PubMed1997

Protective effects of IL-4, IL-10, IL-12, and IL-13 in IgG immune complex-induced lung injury: role of endogenous IL-12.

Using the IgG immune complex (BSA-anti-BSA) model of acute lung injury in rats, we have compared four intratracheally administered cytokines for their protective effects on parameters of injury (albumin leak and hemorrhage) and on neutrophil accumulation (lung content of myeloperoxidase). The descending rank order of protective effects was: IL-10 > or = IL-13 > IL-4 > > IL-12. In animals receiving an intratracheal instillation of 1.0 microg murine rIL-4, IL-10, IL-12 or IL-13, the levels of TNF-alpha in bronchoalveolar (BAL) fluids after intrapulmonary deposition of IgG immune complexes were reduced by 98, 98, 34, and 97%, respectively, implying a corresponding reduction in up-regulation of lung vascular intercellular adhesion molecule-1. The unexpected findings with IL-12 were further evaluated. In spite of reduced BAL levels of TNF-alpha in IL-12-treated animals, BAL levels of IFN-gamma were elevated sixfold, indicative of the expected biologic response to IL-12. Alveolar macrophages obtained from the same animals showed a 68% reduction in formation in vitro of NO2-/NO3-. When rats undergoing intrapulmonary deposition of IgG immune complexes were treated either i.v. or intratracheally with blocking Ab to murine IL-12, there were significant increases in lung permeability and myeloperoxidase values, suggesting that in this model intrinsic IL-12 functions in a regulatory manner. In homogenates of injured lungs, this Ab detected heterodimeric complex, consistent with rat IL-12. These data confirm the ability of certain cytokines to suppress in vivo lung inflammatory responses and underscore the unexpected anti-inflammatory activities of IL-12.

Animals↗
PubMed1997

C5a-dependent up-regulation in vivo of lung vascular P-selectin.

Acute lung injury in rats following systemic activation of complement by i.v. infusion of cobra venom factor (CVF) is known to be P-selectin dependent. In the current studies, infusion of CVF caused the appearance in plasma of C5a (as revealed by ELISA analysis) together with neutrophil chemotactic activity, which was totally blocked by addition in vitro of anti-rat C5a. Using a detector 125I-labeled antibody to rat P-selectin, we have demonstrated quantitative up-regulation in vivo of lung vascular P-selectin in a time-dependent manner after infusion of CVF. This up-regulation was almost completely blocked by prior complement depletion or by the infusion of anti-rat C5a. Platelet depletion did not affect CVF-induced up-regulation of lung vascular P-selectin, indicating that platelets were not the source of P-selectin. These results demonstrate that complement and, specifically, C5a are necessary for up-regulation of lung vascular P-selectin after systemic activation of complement.

Animals↗
PubMed1997

Mycophenolate mofetil for obliterative bronchiolitis syndrome after lung transplantation.

BACKGROUND: The development of obliterative bronchiolitis after lung transplantation portends a poor long-term outcome because of progressive decline in allograft function. There are currently no effective means of treating this condition. METHODS: Thirteen patients in whom obliterative bronchiolitis syndrome developed after lung transplantation were treated with mycophenolate mofetil, an antimetabolite immunosuppressant, at a dose of 1.5 g orally twice daily. Patients were followed up clinically and with pulmonary function testing. RESULTS: Duration of mycophenolate mofetil therapy ranged from 1 week to 24 months (mean duration, 11.4 months). Pulmonary function test results stabilized in the majority of patients with no significant further decline in forced expiratory volume in 1 second. Two patients died of progressive obliterative bronchiolitis, 1 patient is alive with progressive disease, and 1 patient died of an acute infection. The drug was discontinued in 2 additional patients. In no patient did severe leukopenia or cytomegalovirus infection develop; 1 patient had a fungal infection, and 7 patients experienced gastrointestinal side effects. CONCLUSIONS: In the setting of obliterative bronchiolitis syndrome, mycophenolate mofetil is generally well tolerated and is associated with stabilization of pulmonary function test results. These findings suggest that the otherwise progressive process of obliterative bronchiolitis can be slowed.

Adult↗
PubMed1997

Requirement for C5a in lung vascular injury following thermal trauma to rat skin.

Previous studies in rats have shown that deep second degree dermal burns, involving 28-30% of total body surface area, result in systemic complement activation, appearance in plasma of chemotactic activity, sequestration of blood neutrophils in lung capillaries, and development of neutrophil-dependent dermal vascular and lung vascular injury. Although blockade of complement activation or depletion of complement before skin burns has resulted in significant attenuation of tissue injury both locally and distally (in lung), a role for C5a in these events is unclear. In the following studies, we demonstrate the presence of C5a and neutrophil chemotactic activity in serum and in lung homogenates after thermal injury. C5a has also been found in bronchoalveolar lavage fluids of thermally injured animals. Treatment of animals with a polyclonal neutralizing rabbit antibody to rat C5a was lung protective. The protective effects of the antibody (anti-C5a) were associated with diminished vascular permeability changes, as well as reduced tissue build-up of myeloperoxidase. Anti-C5a also prevented up-regulation of lung vascular ICAM-1 (intercellular adhesion molecule-1) in skin-burned rats. These observations indicate that C5a is essential for development of neutrophil accumulation and vascular permeability increases in distant (lung) organs after thermal trauma to skin. The protective effects of anti-C5a in lung, appear to be related to prevention of up-regulation of vascular ICAM-1. Accordingly, C5a may represent a target for clinical approaches in the treatment of organ injury following thermal trauma.

Animals↗
PubMed1996

Requirement and role of C5a in acute lung inflammatory injury in rats.

The complement activation product, C5a, may play a key role in the acute inflammatory response. Polyclonal antibody to rat C5a was used to define the requirements for C5a in neutrophil-dependent inflammatory lung injury after systemic activation of complement by cobra venom factor (CVF) or after intrapulmonary deposition of IgG immune complexes. In the CVF model, intravenous infusion (but not intratracheal instillation) of anti-C5a produced a dose-dependent reduction in lung permeability and in lung content of myeloperoxidase. In C6-deficient rats, CVF infusion caused the same level of lung injury (measured by leak of 125I-albumin) as found in C6-sufficient rats. In the IgG immune complex model of lung injury, anti-C5a administered intratracheally (but not intravenously) reduced in a dose-dependent manner both the increase in lung vascular permeability as well as the buildup of lung myeloperoxidase. Treatment with anti-C5a greatly suppressed upregulation of lung vascular intercellular adhesion molecule-1 (ICAM-1). This was correlated with a substantial drop in levels of TNFalpha in bronchoalveolar fluids. These data demonstrate the requirement for C5a in the two models of injury. In the IgG immune complex model, C5a is required for the full production of TNFalpha and the corresponding upregulation of lung vascular ICAM-1.

Animals↗
PubMed1996

Protective effects of combined adhesion molecule blockade in models of acute lung injury.

In various models of lung inflammatory injury in rats, individual requirements for leukocytic and endothelial adhesion molecules have been established. In the current study dose-response interventions were employed and comparisons made to protective effects of single and dual blockade of adhesion molecules. In lung injury following systemic activation of complement, single blockade of P- or L-selectin produced dose-dependent protective effects, while combined blocking of L- and P-selectin produced protection that was incremental to either blockade alone but less than completely additive. The blocking of selectins seemed to have limited effects. Additive protective effects were also found with dual blockade of CD11a and CD11b. In the IgG immune complex model of lung injury, combined blocking of L- and E-selectin was more effective than blocking of either selectin alone. Combined blockade of CD11a and CD18 was also more effective than either blocking intervention alone. However, blocking of CD11b was ineffective and was not associated with increased protection when combined with anti-CD18, confirming earlier indications that, under the conditions employed, Mac-1 plays no measurable role in this model of lung injury. Increased protection also occurred when mAb to E-selectin was combined with mAb to either ICAM-1 or CD18. In the IgA immune complex model of lung injury the simultaneous blocking of E-selectin and ICAM-1 resulted in protection that was no different from the effects of blocking ICAM-1 alone, confirming that E-selectin plays no role in this model of lung injury. Dual blockade of CD11b and CD18 was more effective than blockade of either alone. Finally, combined blockade of CD18 and VLA-4 in the two models of immune complex-induced injury was more effective than individual blockade. These data substantiate the multiple requirements for adhesion molecules in the three models of lung injury. The findings raise questions as to why dual blockade of adhesion molecules produces less than completely additive effects of the individual interventions and why the protective effects of blocking antibodies seem to have an upper limit.

Animals↗
PubMed1995

Up-regulation of lung vascular ICAM-1 in rats is complement dependent.

Intrapulmonary deposition of IgG immune complexes in rats causes acute inflammatory lung injury that is neutrophil, complement, cytokines (IL-1, TNF-alpha), and intercellular adhesion molecule (ICAM-1) dependent. In the current studies involving the same model of lung injury, complement depletion or complement blockade resulted in substantial reductions in up-regulation of pulmonary vascular ICAM-1, accompanied by reduced lung injury and neutrophil accumulation. Complement depletion neither reduced the amount of immune complex deposited in lung nor the TNF-alpha content in bronchoalveolar lavage fluids. In the same model of inflammatory lung injury, neutrophil depletion (which is highly protective) did not affect up-regulation of lung vascular ICAM-1. Up-regulation of lung vascular ICAM-1 by intratracheally administered TNF-alpha was also prevented by complement depletion. These studies indicate an unexpected in vivo relationship between complement and up-regulation of lung vascular ICAM-1.

Animals↗
PubMed1995

Compartmentalized roles for leukocytic adhesion molecules in lung inflammatory injury.

By using the model of acute injury caused by intrapulmonary deposition of IgG immune complexes, blocking mAb to CD11a, CD11b, L-selectin, and intercellular adhesion molecule-1 (ICAM-1) were administered either i.v. or intratracheally (i.t.). The effects of these interventions were assessed according to lung injury, lung content of myeloperoxidase (MPO), TNF-alpha, and cellular content in bronchoalveolar lavage (BAL) fluids, and up-regulation of pulmonary vascular ICAM-1. In animals treated i.v. with Abs to CD11a, L-selectin, or ICAM-1 lung injury was significantly attenuated in parallel with reduced lung content of MPO. Under similar conditions, treatment with anti-CD11b had no effect. However, when the same mAb were administered i.t., anti-CD11a and anti-L-selectin were without protective effects, whereas i.t. administered anti-CD11b and anti-ICAM-1 were each highly protective. The protective effects of anti-CD11b were related to profound reductions in BAL levels of TNF-alpha, pulmonary vascular up-regulation of ICAM-1, and lung content of MPO. The protective effects of i.t.-administered anti-ICAM-1 were not associated with reduced BAL levels of TNF-alpha. Protective effects of mAb were also reflected in reductions of retrievable neutrophils in BAL fluids. mAb to rat CD11b and CD18 but not to rat CD11a suppressed in vitro production of TNF-alpha by immune complex-stimulated rat alveolar macrophages. The mAb did not reduce NO2-/NO3- generation in stimulated macrophages but all mAb (except anti-ICAM-1) reduced O2- responses in macrophages. These data suggest a compartmentalized role for adhesion molecules in lung inflammatory injury after intraalveolar deposition of IgG immune complexes, with CD11a, L-selectin, and ICAM-1 being important in the vascular compartment for neutrophil recruitment, whereas in the alveolar compartment CD11b and ICAM-1 (but not CD11a and L-selectin) seem to play key roles.

Alveolitis, Extrinsic Allergic↗
PubMed1995

Anti-inflammatory effects of sulfatides in selectin-dependent acute lung injury.

Selectins promote adhesive interactions between leukocytes and activated endothelial cells, the adhesion being mediated by 'counter-receptors' on endothelial cells and consisting of oligosaccharide conjugates containing sialic acid and fucose. There are also suggestions that selectins bind sulfated compounds, including sulfatides. Intravenous infusion of selectin-reactive oligosaccharides has been found to prevent selectin-dependent inflammatory lung injury. In the current studies using two models of neutrophil and selectin-dependent acute lung injury in rats, sulfatide and its modified versions were infused i.v. and the protective effects determined. Naturally occurring sulfatide, synthetic sulfatides and sulfated ganglioside were highly protective against lung injury following systemic activation of complement. Desulfated sulfatide was inactive. The protective effects of synthetic sulfatides required sulfation of galactose in position 3. Sulfatide was also protective in the IgG immune complex model of lung injury. The protective effects of sulfatides were associated with reduced content of myeloperoxidase (derived from neutrophils) in lung tissue. These data indicate that sulfatides have significant in vivo protective effects in neutrophil and selectin-dependent models of lung injury.

Animals↗
PubMed1994

Requirements for L-selectin in neutrophil-mediated lung injury in rats.

L-selectin requirements in three models of acute lung injury in rats have been identified: systemic activation of complement after intravenous infusion of cobra venom factor (CVF) and intrapulmonary deposition of IgG or IgA immune complexes. In the CVF model of lung injury, treatment of rats with hamster monoclonal IgG anti-rat-L-selectin (HRL-1) induced significant neutropenia, necessitating the use of F(ab')2 fragments, which did not cause neutropenia. Treatment of rats with F(ab')2 anti-L-selectin (HRL-1) resulted in significant reductions in lung permeability and hemorrhage in the CVF model. Morphologically, this treatment abrogated adhesive interactions of neutrophils with the pulmonary vascular endothelium. In the IgG immune complex model of injury, the parameters of injury were significantly reduced as a result of treatment with HRL-1. In both models protection was associated with reductions in lung myeloperoxidase content. Treatment of rats with a F(ab')2 form of hamster monoclonal IgG non-blocking anti-L-rat selectin, HRL-2, failed to show protective effects in the CVF and IgG immune complex models of lung injury. In the IgA immune complex model of injury, which is neutrophil-independent and related to toxic products from pulmonary macrophages, no protective effects of anti-L-selectin (HRL-1) were found. Therefore, in neutrophil-dependent and oxygen radical mediated lung injury, L-selectin plays a requisite role in tissue recruitment of neutrophils. In the neutrophil-independent model of lung injury, no requirement for L-selectin appears to exist.

Animals↗
PubMed1994

Role of selectins in local and remote tissue injury following ischemia and reperfusion.

Ischemia (4-hour) followed by reperfusion (4-hour) of rat hind limbs results in local injury as well as remote (lung) injury. It has recently been shown that injury in this model is neutrophil- and cytokine-dependent and requires the beta 2 integrin adhesion molecules CD11a/CD18 and CD11b/CD18. The role of selectins in events leading to injury (as determined by leakage of albumin and by hemorrhage) was assessed either through the use of blocking antibodies to L-, E- or P-selectins or by the use of oligosaccharides that are reactive with selectins. Lung injury was found to be L- and E-selectin-dependent. When the ischemia and reperfusion times were reduced, lung injury was also found to be P-selectin dependent. In the case of hind limb injury involving the crural muscle mass, injury was L-selectin-dependent but independent of requirements for P- and E-selectin. Injury in both organs was blocked by the infusion of sialylated Lewis pentasaccharide, whereas sialyl-N-acetyllactosamine pentasaccharide failed to protect against injury. In general, when selectin-blocking approaches were protective, there were parallel reductions in tissue content of myeloperoxidase. These data underscore the role of selectins in ischemia-reperfusion injury and suggest that selectin requirements may vary with the vascular bed under study.

Animals↗
PubMed1994

Role of leukocyte adhesion molecules in lung and dermal vascular injury after thermal trauma of skin.

Acute second degree thermal injury of rat skin involving 25 to 30% total body surface of anesthetized rats results at 4 hours in evidence of vascular injury both locally (in skin) and remotely (involving lung). The neutrophil dependency for both types of injury has now been established. Monoclonal antibodies to various adhesion molecules have been used to define the requirements for these molecules in the development of vascular injury. In dermal vascular injury, a requirement for Mac-1 (CD11b/CD18) but not for leukocyte function-associated antigen-1 (LFA-1, CD11a/CD18) has been established. In this model requirements have also been demonstrated for intercellular adhesion molecule-1 (ICAM-1) and E- and L-selectin but not for very late arising antigen-4 (VLA-4) or P-selectin. With respect to lung vascular injury, dual requirements for both leukocyte function-associated antigen-1 and Mac-1 were found as well as for ICAM-1 and E- and L-selectin but not for VLA-4 and P-selectin. In the lung, there was a close correlation between neutrophil content of the tissue (as assessed by myeloperoxidase) and the effects of protective interventions (directed against blocking of adhesion molecules). These data emphasize the roles of beta 2 integrins, selectins (L and E), and ICAM-1 in events that lead to neutrophil-mediated vascular injury of dermis and lung after thermal trauma to skin.

Animals↗
PubMed1994

Effects of preservation techniques on in vivo expression of adhesion molecules by aortic valve allografts.

Methods of sterilization and preservation of aortic valve allografts influence graft longevity. The effect of storage techniques on valve durability may be mediated by alterations in the immunologic properties of the allograft, which are reflected by expression of leukocyte adhesion molecules. Rat aortic valve grafts were transplanted in the fresh state, after cryopreservation (-196 degrees C), or after storage at 4 degrees C for 1 to 21 days. Syngeneic and strongly allogeneic valves were transplanted for 4 hours to 21 days and were retrieved for immunohistochemical staining for expression of leukocyte adhesion molecules. Unimplanted valves and transplanted syngeneic valves, regardless of storage methods, exhibited little or no expression of leukocyte adhesion molecules. Fresh allogeneic valves expressed all molecules, indicating up-regulation, at all time intervals studied. Cryopreserved allogeneic valves demonstrated no leukocyte adhesion molecules at 4 hours or 2 days and weak reactivity at 10 and 21 days. Allogeneic valves stored at 4 degrees C, regardless of the duration of storage, demonstrated weak expression of all molecules at 10 days and strong expression at 21 days. Expression of leukocyte adhesion molecules requires an allogeneic environment and may precede immune-mediated injury. Reduced expression of leukocyte adhesion molecules resulting from storage may predict a diminished immunologic response. Cryopreservation (-196 degrees C) causes the greatest delay and diminution of expression of leukocyte adhesion molecules.

Animals↗
PubMed1993

In vivo suppression of immune complex-induced alveolitis by secretory leukoproteinase inhibitor and tissue inhibitor of metalloproteinases 2.

The pulmonary tree is exposed to neutrophil-derived serine proteinases and matrix metalloproteinases in inflammatory lung diseases, but the degree to which these enzymes participate in tissue injury remains undefined, as does the therapeutic utility of antiproteinase-based interventions. To address these issues, an in vivo rat model was examined in which the intrapulmonary deposition of immune complexes initiates a neutrophil-mediated acute alveolitis. In vitro studies demonstrated that rat neutrophils can release neutrophil elastase and cathepsin G as well as a neutrophil progelatinase, which was subsequently activated by either chlorinated oxidants or serine proteinases. Based on structural homologies that exist between rat and human neutrophil proteinases, rat neutrophil elastase and cathepsin G activities could be specifically regulated in vitro by recombinant human secretory leukoproteinase inhibitor, and rat neutrophil gelatinase activity proved sensitive to inhibition by recombinant human tissue inhibitor of metalloproteinases 2. When either of the recombinant antiproteinases were instilled intratracheally, in vivo lung damage as assessed by increased permeability or hemorrhage was significantly reduced. Furthermore, the coadministration of the serine and matrix metalloproteinase inhibitors almost completely prevented pulmonary damage while effecting only a modest decrease in neutrophil influx. These data support a critical role for neutrophil-derived proteinases in acute lung damage in vivo and identify recombinant human secretory leukoproteinase and recombinant human tissue inhibitor of metalloproteinases 2 as potentially efficacious interventions in inflammatory disease states.

Animals↗
PubMed1993

Protective effects of selectin chimeras in neutrophil-mediated lung injury.

Recombinant selectin chimeric molecules featuring the joining of the extracellular domains of L-, P-, and E-selectin to the CH2 and CH3 domains of human IgG1 have been evaluated for their ability to protect against neutrophil-dependent lung injury in rats after systemic activation of C caused by vascular infusion of cobra venom factor (CVF) or lung injury that follows intrapulmonary deposition of IgG immune complexes. Previous studies using anti-selectin antibodies have suggested that the former model is P-selectin dependent, whereas the latter is E-selectin dependent. Requirements for L-selectin have not been identified because of lack of reagents. For the current studies employing the CVF model of lung injury, infusion of P-selectin-Ig chimera reduced injury (as assessed by changes in permeability and hemorrhage) in a dose-dependent manner, with parallel reductions in lung myeloperoxidase (MPO) content. Similar results were obtained with the L-selectin-Ig chimera, whereas the E-selectin-Ig chimera was not protective and failed to alter MPO content. In contrast, in the IgG immune complex model of lung injury, the L- and E-selectin-Ig chimeras both showed dose-related protective effects and reductions in MPO content, whereas the P-selectin-Ig chimera failed to protect against injury and did not alter MPO content in this model of lung injury. In all cases of blocking of injury, this was incomplete, suggesting multi-selectin engagement or inadequate amounts of selectin-Ig chimeras employed. These data indicate that neutrophil recruitment and attendant lung injury in the CVF model are L- and P-selectin dependent and E-selectin-independent, whereas in the IgG immune complex model, neutrophil recruitment and lung injury are L- and E-selectin-dependent but independent of P-selectin. Thus, differing selectin requirements for acute inflammatory lung injury have been identified.

Animals↗
PubMed1993

Protective effects of IL-4 and IL-10 against immune complex-induced lung injury.

Recombinant murine IL-4 and IL-10 have been used in two models of inflammatory lung injury in rats after intrapulmonary deposition of IgG or IgA immune complexes. These models have contrasting requirements for cytokines, phagocytic cells, and adhesion molecules. In these two models of lung injury, IL-4 and IL-10 were individually coinstilled into the airways with the IgG or IgA antibodies, whereas the Ag were injected intravenously. Injury was quantitated by increases in permeability (leakage of 125I-BSA) and by hemorrhage (extravasation of 51Cr-RBC). In the model of IgG immune complex-induced lung injury, IL-4 and IL-10 were each highly protective when given in nanogram amounts. These protective effects were dose dependent. IL-4 and IL-10 caused substantial reductions in lung content of myeloperoxidase and parallel reductions in neutrophil content in bronchoalveolar lavage (BAL) fluids. The protective effects of IL-4 and IL-10 were associated with profound reductions of TNF-alpha in the BAL fluids and complete inhibition in the up-regulation of pulmonary vascular ICAM-1. In the IgA immune complex model of lung injury IL-4 had no protective effects, whereas IL-10 was highly protective. These protective effects correlated with diminished retrieval of alveolar macrophages in BAL fluids. These data suggest that IL-4 and IL-10 have significant protective effects in lung inflammatory injury, presumably achieving these effects by various mechanisms.

Animals↗
PubMed1993

Protective effects of sialylated oligosaccharides in immune complex-induced acute lung injury.

Using sialyl Lewisx (SLX) oligosaccharides derived from fucosyl transferase-expressing cells or generated synthetically, the ability of these compounds to protect against acute lung damage after deposition of immunoglobulin (Ig)G or IgA immune complexes has been determined. The synthetic compounds were tetra- and pentasaccharide derivates of SLX as well as the nonfucosylated forms of SLX as controls. In the IgG immune complex model of lung injury, which is E-selectin dependent, SLX preparations provided dose-dependent protective effects, as assessed by changes in lung vascular permeability and hemorrhage. Protective effects were associated with diminished tissue accumulation of neutrophils in lungs (as assessed by myeloperoxidase). Morphological assessment revealed reduced physical contact of neutrophils with the pulmonary vascular endothelium and reduced tissue accumulation of neutrophils. In the model of IgA immune complex-induced lung injury, which does not involve participation of neutrophils and is independent of the requirement for E-selectin, SLX preparations were not protective. These data suggest that, in neutrophil-mediated and E-selectin-dependent lung injury, SLX preparations provide significant, protective effects against inflammatory vascular injury. The ability to achieve antiinflammatory outcomes in vivo with appropriate oligosaccharides suggests a new approach to the blocking of acute inflammatory responses.

Acute Disease↗