Biomedical subjects

M W Baseler

Publications and source records attributed to M W Baseler.

22 records · Page 2Linked to original sources

PubMed1986

A new class of synthetic biological response modifiers: the methylfurylbutyrolactones (Nafocare B).

A new class of synthetic biological response modifiers (BRMs) has been produced by combining a highly electrophilic reactant, 2-methyl-2, 5-dihydrofuran (a cyclic acetal of cis-3-acetyl acrolein), with L-ascorbic acid. The parent class of compounds can be referred to as methylfurylbutyrolactones (MFBL), previously termed Nafocare B. This parent molecule is amorphous, has a molecular weight of 252.7, and the chemical name [3,6] cyclohemiketal of 2-(5-methyl-2-furyl)-3-keto-L-butyrolactone. Two crystalline forms were produced by a reaction of the MFBL parent molecule with either succinic anhydride or succinimide, to create MFBL-SA (Nafocare B2) and MFBL-S (Nafocare B3) dimers, respectively. The structure of these compounds has been confirmed by modern methods of analytical chemistry, including x-ray crystallography. All three forms of the MFBLs showed negligible toxicity in single-dose acute LD-50s in mice. Also, the MFBLs did not demonstrate genotoxic activity at 800 mg/kg in the mouse micronucleus assay. The MFBLs are immunostimulatory in assays involving T- and B-lymphocytes, but not in immunoassays on macrophages derived from resident- or thioglycollate-elicited peritoneal exudate cells (PEC). Spleen cells from mice treated 4 days via the intraperitoneal, intravenous, or the oral routes responded significantly over controls to suboptimal stimulatory concentrations of polyclonal mitogens in the lymphocyte stimulation assay. The MFBLs were not mitogenic, since they did not increase DNA synthesis in resting spleen cells from MFBL-treated mice. Antibody production is also amplified by the MFBLs. Mice immunized with sheep erythrocytes, a T-cell-dependent antigen, and treated with MFBLs had a 200-800% increase in the numbers of antibody-producing splenic lymphocytes detected by the Jerne hemolytic plaque assay. Also, mice immunized with soluble bovine serum albumin (BSA), and treated with a MFBL, demonstrated at least a fourfold increase in IgG-specific antibodies to BSA, when compared with controls. To demonstrate effects of MFBLs on macrophages, we used the Fc receptor (FcR) surface marker and superoxide anion assays. Only at the highest in vitro dose of MFBL (16 micrograms/ml) was a significant increase in erythrocyte antibody rosette formation detected, using resident macrophages isolated from PEC. In the superoxide anion release assay neither resident- nor thioglycollate-elicited PECs, obtained from in vivo-treated mice or macrophages treated in vitro, showed increased production of superoxide anion.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldehydes↗

PubMed1983

Purification of haptoglobin and its effects on lymphocyte and alveolar macrophage responses.

Clinical observations made on a patient with acute hypersensitivity pneumonitis revealed that the patient's serum contained a mitogenic inhibitor and an extremely high haptoglobin (Hp) level; this led to an investigation of the role of Hp in lymphocyte function. Hp was isolated and purified from acute phase rabbit serum by a new method using DE-52 anion exchange chromatography and preparative isoelectric focusing in a range of pH 3.0-5.0. This technique produced a homogenous, biologically active product in fewer steps and in higher yields than existing techniques. Purified rabbit Hp significantly inhibited polyclonal lymphocyte mitogenic responses to PHA or Con A in a dose-response fashion. Hp also significantly inhibited B-cell mitogenesis at a high concentration (200 mg/100 ml) in response to LPS while it enhanced B-cell mitogenesis at lower concentrations (50 and 100 mg/100 ml). Purified Hp had no effect on monoclonal, antigen-specific (BSA) mitogenesis. Rabbit alveolar macrophages produced significant amounts of prostaglandin E in vitro in response to LPS but Hp had no effect on this production. However, Hp alone caused approximately the same amount of stimulation of PGE production by alveolar macrophages as did LPS alone. The ability of Hp to modulate lymphocyte as well as macrophage function seems to indicate that Hp plays a role in the moderation of inflammation. This ability to moderate inflammation, especially in the lungs, may play an important role in regulating tissue damage and disease following inhalation of inflammatory aerosols.

Alveolitis, Extrinsic Allergic↗

PubMed1983

Differential toxicity of inhaled gram-negative bacteria.

The toxicity by inhalation of various gram-negative bacteria, isolated from settings associated with inhalation disease, was studied by a variety of means. These microorganisms were not equally toxic. Citrobacter freundii aerosol challenges of rabbits provoked significant (up to fivefold) increases in plasma haptoglobin 24 to 48 h after inhalation. Other strains tested failed to provoke such statistically consistent increases. Measurements of C-reactive protein in these same animals did not lead to as reliable results, due to the variability of the responses. Mice responded differently to inhalation in that haptoglobin responses were either unaffected or depressed. When a strain of mice was used that exhibits more severe inflammatory responses to endotoxin (C3H/HeJ), C. freundii and Escherichia coli aerosols provoked significant haptoglobin increases. Free lung cell analyses demonstrated that the macrophage and neutrophil responses differed depending on the strain of bacteria used. Again, C. freundii induced the greatest responses. When murine B lymphocytes were stimulated with lipopolysaccharide preparations from different gram-negative bacteria, distinctly different dose-response curves were obtained. The types of responses obtained indicate that (i) brief inhalation of bacterial aerosols previously thought to be innocuous may lead to pulmonary inflammation, and (ii) that these bacteria differ in their toxicity, with C. freundii being the most toxic organism of the five studied.

Aerosols↗

PubMed1981

Acute-phase reactants in experimental inhalation lung disease.

An investigation on the occurrence and role of acute-phase reactants in experimental inhalation lung disease (ILD) was undertaken. Using an experimental model of ILD in which rabbits are exposed to aerosols of appropriate fungal spores, haptoglobin analysis was compared with depressions in arterial oxygen tension (PaO2) with time following challenge. Haptoglobin values of rabbits exposed to single 30-min aerosol challenges of Aspergillus terreus, demonstrated a significant (two- to three fold) increase 24-48 hr after challenge. Haptoglobin elevation was found to be a more reliable and consistent indicator of pulmonary inflammation than depression of PaO2. In an effort to determine the role of haptoglobin in this response, acute phase reactant levels were elevated either actively or passively. When rabbits with augmented haptoglobin levels were exposed to aerosol challenges with A. terreus, the typical depressions in PaO2 at 1-4 hr postchallenge were not observed. This indicated the plasma containing elevated acute-phase reactants may be involved in limiting the pulmonary response that normally occurs following challenge. Haptoglobin was not found to bind to A. terreus spores in vitro.

Aerosols↗