Biomedical subjects
Publications and source records attributed to R C Strunk.
Although the clinical features of exercise-induced asthma (EIA) have been clearly described, the pathophysiology is incompletely understood. This review addresses some of the current concepts about the pathogenetic mechanisms of EIA and their implications for treatment of this problem.
gamma-Interferon (IFN-gamma) is a well characterized lymphokine known to regulate many mononuclear phagocyte functions, including expression of class I and class II major histocompatibility complex genes. The second component of complement (C2) and factor B are major histocompatibility complex class III gene products synthesized in mononuclear phagocytes. Recombinant IFN-gamma increased the synthesis of C2 and factor B in primary cultures of human mononuclear phagocytes and in murine fibroblasts transfected with cosmid DNA bearing the human C2 and factor B genes. In both cell types the increases in C2 and factor B protein synthesis were detected at concentrations of IFN-gamma less than 1 unit/ml and the regulation of each was pretranslational. The IFN-gamma-induced increases in C2 and factor B mRNA did not require new protein synthesis. In primary cultures of human monocytes, the kinetics of induction of C2 and factor B synthesis differed, but in the transfected L-cells the kinetics were similar, suggesting differences in transduction of the IFN-gamma signal, transcriptional, and/or post-transcriptional events in the two cell types. The small size of the factor B 5' flanking region, which is bounded by the 3' terminus of the IFN-gamma-regulated C2 gene, provides a well defined region to probe the structural basis for IFN-gamma regulation of gene expression.
Several reports have documented characteristics of children who die of asthma; however, to the best of our knowledge, no studies have used case controls to clarify the clinical characteristics associated with death. We conducted a case-controlled study of 21 patients with severe asthma hospitalized between 1973 and 1982 who died of asthma sometime following discharge. Average age at death was 13 years (range, 8 to 18 years). Twenty-one asthmatic control cases were matched for age at the time of hospitalization, sex, and severity of illness. Hospital records were evaluated for 57 physiologic and psychological variables. A stepwise discriminant analysis determined that the following eight variables could discriminate the two groups effectively: history of seizures associated with an asthma attack; conflicts between the patient's parents and hospital staff regarding medical management of the patient; self-care of asthma while in the hospital that was not appropriate for age; prednisone dosage having been decreased by more than 50% during the course of hospitalization; inhaled beclomethasone dipropionate required for treatment; increased asthmatic symptoms during the week preceding discharge; depressive symptoms; and disregard of asthmatic symptoms. Most of the clinical characteristics previously thought to place patients at greater risk for a fatal asthmatic attack were found as often in the control cases as in the children who died. This study indicates that psychologic risk factors were prominent in severely asthmatic children who subsequently died of asthma. The variables defined in this study may be important in identifying patients who are at high risk for dying of asthma and in developing treatment plans to prevent deaths.
Activation of the third component of complement (C), C3, is central to the functioning of the C system in inflammation. Cleavage of C3 by the C3 convertases of both the classical and alternative pathways results in the formation of two split products, C3b and C3a. C3a inhibited cleavage of C3 by the classical-pathway C3 convertase. The inhibition varied in a concn-dependent relationship, with a concn of approximately 40 micrograms/ml yielding 50% inhibition. Removal of the carboxy terminal arginine from the C3a did not alter the inhibition. C3a did not inhibit cleavage of C3 by the alternative C pathway C3 convertase, or cleavage of C5 by C5 convertase. The C3-cleaving capacity of EAC142oxy that had been previously incubated with C3a could be recovered completely by washing the cells, indicating that the C3a binding to the EAC42oxy cell must have been reversed without having had an effect on the amount of C2 bound. Ribonuclease, a molecule of similar size and charge to C3a, did not affect C3 cleavage and C3a inhibition was not reduced by providing a surface for non-specific adsorption of the C3a, suggesting that the effect of C3a on C3 cleavage was not mediated by non-specific interaction with cell surfaces. C3a inhibited the C3-cleaving capacity of the fluid-phase enzyme, C42oxy, to the same degree as it inhibited the cell-bound enzyme, EAC42oxy, indicating that the C3a must interact with the C42 complex directly. Inhibition of C3 cleavage by C3a is the first demonstration of product inhibition of a complement enzyme. It may provide another control of C3 activation.
The effect of soybean oil emulsion (Intralipid) therapy on serum complement levels was determined in infants who received Intralipid therapeutically (1 gm/kg over 12 hours, every other day). The effect of Intralipid on macrophage priming for increased superoxide anion production was studied in a mouse model. Intralipid administration did not affect either macrophage function. Serum levels of C2 and C4, complement components synthesized and secreted exclusively in macrophages, were not decreased either during the week the infants received Intralipid or in the week following administration. Macrophages from mice that had received Intralipid produced similar amounts of superoxide anion, as did macrophages from mice that had received saline solution. Our data suggest that macrophages in infants receiving Intralipid in this regimen will function normally.
Explore the source record for details and available documents.
The third component of complement (C3) is a plasma glycoprotein with a variety of biologic functions in the initiation and maintenance of host response to infectious agents. While the hepatocyte is the primary source of plasma C3, mononuclear phagocytes contribute to the regulation of tissue availability of C3. Lipopolysaccharide (LPS), a constituent of cell walls of gram-negative bacteria, consists of a polysaccharide moiety (core polysaccharide and O antigen) covalently linked to a lipid portion (lipid A). Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-polyacrylamide gel electrophoresis, we examined the effects of LPS on synthesis of C3 by human mononuclear phagocytes as well as synthesis of the second component of complement (C2), factor B, lysozyme, and total protein. LPS increased C3 synthesis 5-30-fold without affecting the kinetics of secretion of C3 or the synthesis of C2, lysozyme, or total protein. Factor B synthesis was consistently increased by LPS. Experiments with lipid A-inactivated LPS (alkaline treated), LPS from a polysaccharide mutant strain, and lipid X (a lipid A precursor) indicated that the lipid A portion is the structural element required for this effect. Northern blot analysis demonstrated at least a fivefold increase in C3 mRNA in LPS-treated monolayers, which suggests that the regulation of the increase in C3 synthesis is pretranslational. C2 mRNA and factor B mRNA were increased approximately twofold. The availability of specific gene products in human mononuclear phagocytes that respond to LPS should permit understanding of the molecular regulation of more complex functions of these cells elicited by LPS in which multiple gene products are coordinately expressed.
Concentrations of five serum proteins, C3, C5, ceruloplasmin, C-reactive protein, and albumin, have been measured during the acute phase response in rabbits with turpentine-induced pleurisy. C-reactive protein concentrations in the circulation rose abruptly between 12 and 36 hours to a level greater than 50 times the pretreatment concentration, then returned to undetectable amounts by 96 hours. C3 and ceruloplasmin both showed some increase in concentration by 12 hours and reached their maximum concentrations of two to three times the baseline levels 48-72 hours after the turpentine treatment. Concentrations were still elevated at 120 hours, after which time they gradually returned to normal. C5 and albumin concentrations in the turpentine-treated rabbits did not differ from the baseline concentrations. The same five proteins were measured in the inflammatory exudate. C-reactive protein was not detectable at any of the time points. C3, C5, ceruloplasmin, and albumin were present in normal pleural fluid at roughly half their serum concentrations. The activities of C3, C5, and ceruloplasmin were low in the early exudate, but C3 and C5 activity rose relative to their concentrations in the later samples of pleural fluid. The specific activities of C3 and C5 were higher in the pleural fluid at 72 hours than in plasma, while that of ceruloplasmin remained less in the pleural fluid than in plasma throughout the experiment. The involvement of these proteins and their relation to the inflammatory response are discussed.
Since LARs are associated with increases in airways reactivity, their significance may go well beyond the increase in symptoms due just to the allergen exposure. This is especially true since the increase in non-specific airways reactivity can last for weeks after a single exposure to allergen. Every effort should be made to search for possible allergic triggers in patients suspected to have LARs. Careful attention to historical information and skin test reactivity are critical in this evaluation. In situations where this approach is not revealing and where serious concerns remain about potential environmental triggers, a bronchial challenge to the suspected antigen can be considered. Since the nonspecific airways reactivity in patients with LAR may possibly be due to inflammation in the airways, the potential risk of transient induction of airways inflammation must be carefully weighed against the value of information that can be obtained from this procedure. Bronchial challenge should be performed only in an inpatient setting by experienced personnel under the supervision of a physician. A full explanation of the potential risks and benefits of this type of evaluation must be given to the patient and family. Treatment is primarily directed at allergen avoidance with use of a prophylactic drug, such as cromolyn sodium, when allergen avoidance is not possible.
Fifty-three children with moderately severe asthma were studied to determine the capacity of drugs to block exercise-induced bronchospasm (EIB). All 53 children demonstrated EIB (as defined by a 20% fall in FEV1 or 30% fall in FEF25-75) while receiving therapeutic theophylline (serum level 10-20 micrograms/ml). EIB was completely blocked in 47 children by an inhaled metaproterenol 10 minutes prior to exercise, in addition to the theophylline. In six children, EIB was only partially blocked when either metaproterenol or cromolyn was added to the theophylline, but was completely blocked when all three drugs were used. A small group of children may benefit from combination therapy for EIB.
Adverse reactions to aspirin in asthmatic patients have been widely described in the past. In contrast to this more frequent complication, several authors have published reports suggesting that aspirin and other nonsteroidal anti-inflammatory drugs can improve asthma. We studied the effect of long-term aspirin administration in children with moderately severe asthma. Ten children who showed no immediate effect of aspirin challenge (either adverse or beneficial) were placed in a 9 wk, double-blind crossover study, receiving aspirin (10 gr twice daily) or placebo for 4 wk, then a 1 wk washout period, followed by aspirin or placebo for 4 wk. There was no difference between aspirin and placebo periods in number of wheezing episodes, frequency of additional bronchodilator or prednisone use, or daily spirometric measurements. Serum thromboxane B2 levels were significantly reduced during aspirin therapy (p less than 0.001), indicating that the patients had complied with the aspirin therapy. Thus long-term administration of aspirin to asthmatics who show no immediate beneficial or adverse response to aspirin challenge appeared not to influence the clinical course of asthma. In addition, inhibition of the platelet prostaglandin cyclooxygenase pathway in these patients did not modify the clinical course of their asthma.
The use of medications in metered-dose aerosol form in children with asthma has increased dramatically with the development of safer, inhaled beta 2-adrenergic agents and the inhaled corticosteroid, beclomethasone dipropionate. However, the most appropriate techniques of administration of these agents are presently unclear, and frequent inefficient use of these metered-dose inhalers results. We review the aerosol physiology literature to determine and recommend a most efficient inhalation technique for the use of these metered-dose aerosol devices.
The role of complement components in binding of aggregated human gamma globulin (AHG) to Raji cells was examined using the Raji cell radioimmunoassay. Incubation of AHG in normal human serum enhanced up to five-fold the binding of these complexes by Raji cells. This enhanced binding was medicated primarily by C3 receptors, however, as much as 30% of the enhanced binding was due to a heat-labile protein in serum. AHG incubated with serum-EDTA bound to Raji cells up to two-fold more than AHG incubated with unchelated serum. Since purified Clq also enhanced binding, binding of AHG after incubation with serum-EDTA was probably mediated by Clq. The enhancement effected by Clq occurred only if Clq bound first to AHG, not to the Raji cells, and if Clq bound in the absence of Clr and Cls. Speculations on a role for Clq in biological processes must consider whether the Clq in serum is available to participate. The results presented here suggest that whole serum activated by AHG contained only a small amount of Clq available for cross-linking of particles. Thus, the potential involvement of Clq in biological reactions in vivo is probably limited.
Recently a soybean oil emulsion (Intralipid) (IL) has been released in the United States for use as a parenteral nutrient. The study reported here was undertaken to determine the effect of ingestion of IL on the synthesis and secretion of the second (C2) and fourth (C4) components of complement by guinea pig peritoneal macrophages in vitro. Cells exposed to IL had extensive Oil Red 0-positive granular-appearing accumulations of neutral lipid within the cytoplasm. Control cells did not stain with Oil Red 0. Incubation of the cells with concentrations of IL from 2.3--37.5 mg/100 ml resulted in a significant decrease in the production of both C2 and C4, which could not be explained by variability between plates. The decrease in total C2 or C4 production by cells incubated with IL for 4 hr was similar to the decrease in production by cells incubated with IL for 48 hr. Several lines of evidence indicated that the decrease of C2 or C4 was the result of decreased synthesis of these proteins and not interference of IL with the detection of the proteins or their secretion from the cells. Exposure of the cells to IL at all concentrations caused reduction of the number of cells having pseudopodia and a rounding-up of the cells. IL did not affect the rate of detachment of the cells from the plates through the 48-hr incubation period or the ability of the cells to exclude trypan blue. Total protein synthesis and total lysozyme production by control and IL-treated cells was similar.
Classical and alternative pathway complement levels were measured in the cord blood sera of 60 newly born infants, with weights ranging from 1200--4165 g. The impact of maternal illness and infant illness on the complement levels was also evaluated. The mean values for CH50, C3, C4, PH50, factor B, and properdin were all significantly less than normal adult levels (P less than 0.0001). All of the above determinations were significantly correlated with one another except for the relationship between properdin and factor B. CH50, PH50, C4, and properdin levels were significantly correlated with birth weight although there was much residual scatter. Neither maternal illness nor mild to moderate illness in the newborn altered the birth weight-complement relationships. Severe infant illness did significantly alter the relationship between birth weight and complement. However, the impact of this variable on the birth weight-complement relationships was not consistent among the various components. These inconsistencies and the small sample size preclude drawing any strong conclusions about severe illness and complement levels.
Immunofluorescence was performed on lung tissue obtained at necropsy from 18 newborn infants, including five with group B streptococcal (GBS) sepsis, seven with idiopathic respiratory distress syndrome (IRDS), and six control infants who died from other causes. Deposits of C3, IgG, and fibrin were found within hyaline membranes of infants who died with GBS sepsis or IRDS within 48 hours after birth. In some cases C4, factor B, and IgM were also observed. In five infants with IRDS who died more than five days after birth, immunofluorescent lung findings were less common and less intense. Hyaline membranes, attributed to mechanical ventilators and oxygen therapy in two infants who did not have GBS infection or IRDS, were negative for complement and immunoglobulins although fibrin was detected in one specimen. These data suggest that immunologic processes may contribute to the pathogenesis of certain types of acute lung injury, particularly in infants who die from GBS infection or IRDS during the early neonatal period.
Studies in humans who have received Intralipid (IL) have demonstrated the presence of a fat pigment and fat droplets in reticuloendothelial phagocytic cells. Clinical data and in vitro studies suggest that these cells do not function normally. We have studied the effect of IL on the morphology and function of guinea pig peritoneal macrophages in vitro. Starch-induced macrophages were exposed to IL for up to 48 hours. Ingestion of increasing amounts of IL over the 48-hour period was confirmed by transmission electron microscopy and by oil red O stain. The uptake of the IL was associated with marked morphologic changes characterized by a decreased ability of the cells to spread and by a decrease in the number and degree of complexity of the membrane ruffles. The ingestion of IL also resulted in decreased capacity of the cells to associate with latex beads (5.7 mu in diameter) or Candida albicans and decreased capacity to adhere to and ingest sheep erythrocytes coated with IgG. After ingestion of latex beads 0.46 mu in diameter, which are similar in size to IL particles, macrophages had normal morphology and function, indicating that neither the morphologic nor functional abnormalities were due to a nonspecific effect of ingestion of small particles. Alterations of human reticuloendothelial macrophage function similar to the effects observed here could compromise host defense against infection.
Explore the source record for details and available documents.