Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology characterized by the expansion of activated oligoclonal CD4+ T cells and macrophages at sites of disease. To investigate the immunopathogenesis of sarcoidosis, we analyzed patterns of cytokine expression in bronchoalveolar lavage cells and fluid from patients with pulmonary sarcoidosis and idiopathic pulmonary fibrosis and from normal volunteers. We found dominant type 1 cytokine expression, with elevated mRNA and protein levels of IFN-gamma, but not IL-4, in sarcoid lung cells and fluid compared with those in normal samples. To define immunoregulatory mechanisms important to this type 1 response, we analyzed the expression of IL-12 and IL-10 in lung cells and fluid. Using semiquantitative PCR, we found significantly higher mRNA expression of the regulated IL-12 p40 subunit, but not IL-10, in sarcoid compared with normal lung cells. Consistent with these observations, strikingly elevated levels of p40 protein were found in sarcoid compared with normal bronchoalveolar lavage fluid. Unstimulated and Staphylococcus aureus-stimulated sarcoid alveolar macrophages produced greater amounts of IL-12 than normal alveolar macrophages when cultured in vitro. We hypothesize that sarcoidosis is a Th1-mediated disease driven by chronic, dysregulated production of IL-12 at sites of disease.

Exercise testing, 6-min walk, and stair climb in the evaluation of patients at high risk for pulmonary resection.

To evaluate three types of exercise testing in prediction of death or prolonged mechanical ventilation after lung resection in high-risk patients, 16 patients underwent evaluation prior to resection. Eleven patients (group 1) had minor or no complications (arrhythmia, atelectasis, pneumonia) and five patients (group 2) died within 90 days of surgery. Exercise testing showed that group 1 had a longer 6-min walk distance and a higher stair climb than group 2. The maximum oxygen uptake on a cycle ergometer was not significantly different between groups, although only ten patients completed this test. Group 1 had a significantly greater calculated oxygen uptake with stair climbing than group 2. A 6-min walk distance of greater than 1,000 feet and a stair climb of greater than 44 steps were predictive of successful surgical outcome. Preoperative exercise testing is a useful adjunct to traditional spirometric testing in evaluation of the high-risk surgical patients.

Quantum yield values for the decomposition of several surface-active photoreactive amphiphiles.

The quantum yield values for the decomposition of 12-azido-1-diazo-2-dodecanone, 1-diazo-11-dodecanone, 1-diazo-17-octadecen-2-one, stearoyl azide and 10-undecenyl azidoformate in hexane were determined. It was found that the compounds decomposed with relatively high quantum yields, suggesting their use in biological applications, especially for binding phospholipids to membrane proteins.

Evaluation of wheezing in the nonasthmatic patient.

Wheezing is a nonspecific manifestation of airway obstruction. Even though bronchial asthma is the most common cause of wheezing, a variety of pulmonary and nonpulmonary conditions can present with this symptom. In recent years methacholine provocation challenge has simplified detection of bronchial asthma; however, establishing accurate diagnosis of other causes of wheezing is important because each condition requires specific treatment. This article describes a methodical approach to the diagnosis of wheezing in patients who are not asthmatic.

Antagonism of the pulmonary effects of the peptidoleukotrienes by a leukotriene D4 analog.

4R-hydroxy-5S-cysteinylglycine-6-Z-nonadecenoic acid (4R,5S, 6Z-2-nor-LTD1), a structural analog of leukotriene (LT) D4 (LTD4), significantly antagonized the pulmonary actions of LTD4 in several guinea pig models of LT-mediated bronchoconstriction and edema formation. In vitro, 4R,5S,6Z-2-nor-LTD1 (10(-5) and 10(-4) M) antagonized the LTD4-induced contraction of tracheal spirals and lung parenchymal strips. This antagonist action of 4R,5S,6Z-2-nor-LTD1 was specific for the LTs, in that LTC4- and LTE4-induced contractions of the trachea were also antagonized, whereas the contractions elicited by other spasmogens, e.g., histamine, carbachol, prostaglandin F2 alpha and KCl, were not antagonized. In vivo, the LTD4-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs as reflected by decreases in dynamic lung compliance and airway conductance were attenuated significantly by a 1-min pretreatment with 4R,5S,6Z-2-nor-LTD1 at 5 mg/kg i.v. Similarly, the LTD4-induced increase in tracheal microvascular permeability, as assessed by extravasation of [125I]bovine serum albumin, was blocked by pretreatment with 4R,5S,6Z-2-nor-LTD1. These results provide the first demonstration that a structural analog of the peptidoleukotrienes can pharmacologically antagonize the potent actions of these LTs.

Effect of extracts of Angelica polymorpha on reaginic antibody production.

An aqueous extract of Angelica polymorpha was examined for its immunoregulating properties. Its effect on the production of antibodies was tested in (C57BL/6 X DBA/2)F1 mice. When the animals were treated daily with the extract, the serum titers of reaginic antibodies normally observed after a single injection dinitrophenylovalbumin (DNP3-OA) were significantly lower, and the higher and more sustained reaginic titers induced by booster injections of DNP3-OA were also inhibited. The immunosuppressive activity was observed both by oral and intraperitoneal administration of the extract, and it was not removed by dialysis. In contrast, the serum titers of IgG were not significantly altered by the administration of the extract. The extract had little or no effect on the passive cutaneous anaphylaxis reaction or the release of histamine from sensitized rat lung fragments.

Effect of histamine agonists and antagonists on the production of murine reaginic antibodies.

At least wo histamine receptors have been pharmacologically defined. Using the appropriate agonists and antagonists, the possible involvement of these receptor types in the production of reaginic antibodies in the rodent was investigated. After injecting mice with dinitrophenyl-ovalbumin (DNP-OA), maximal serum reaginic titers occurred on day 11 as measured by heterologous passive cutaneous anaphylaxis. If the mice were dosed daily (i.p.) with the H1 agonist, 2-methylhistamine, or the H2 antagonist, metiamide, the titers of reaginic antibodies on day 11 were significantly higher than the controls. The titers were significantly lower than the controls if an H2 agonist (4-methylhistamine, dimaprit, or impromidine) or if the H1 antagonist, pyrilamine, was administered daily. None of these agents significantly affected total serum IgG titers as measured by ELISA. However, if the mice were injected with DNP-OA on day 0, then dosed daily with metiamide, pyrilamine, or 4 methylhistamine beginning on day 32, the titers of reaginic antibodies elicited by a second injection of DNP-OA given on day 36 were not significantly different from the titers of the non-drug treated mice. Thus, under these conditions, with these agents, the results suggest that histamine receptors may be involved in modulating the production of reaginic antibodies during a primary immunological response, H1 receptor agonists enhanced, while H2 receptor agonists suppressed the responses, and the reverse effect was observed with the appropriate antagonists. However, histamine receptors appear not to be measurably involved in the development of the secondary reaginic response.

Effect of kallidin, substance P, and other basic polypeptides on the production of respiratory macromolecules.

When canine tracheal explants were incubated in culture medium 199 in the presence of D-glucosamine labeled with carbon-14 for 24 hours, a significant amount of radioactivity was found in the secreted macromolecules. When kallidin was present in the culture medium, the amount of radioactivity associated with a portion of these macromolecules was increased. A met-lys-bradykinin derivative had a similar effect, but bradykinin did not. When hexadimethrine, an inhibitor of kinin formation, was present in the culture medium, the amount of radioactivity in the macro-molecular fraction was decreased. Substance P and the structurally related polypeptides, physalaemin and eledoisin, also enhanced the production of tracheal macromolecules; they were several-fold more active than kallidin. The effect of polypeptides on the activities of glycosyltransferases was also investigated. One of the enzymes present in a microsomal fraction prepared from the mucosal lining of canine trachea was uridine diphosphate (UDP)-galactose:mucin galactosyltransferase, which required a 25 mM concentration of maganese ions to be present in the assay mixture to obtain maximal enzymatic activity. When the concentration of manganese ions was decreased to 2.5 mM, there was less than one third of the maximal enzymatic activity, but full activity could be restored by the addition of kallidin. Several other basic polypeptides had a similar effect on the enzymatic activity. Kallidin had little or no effect on the activities of several other glycosyltransferases. The results suggest that basic polypeptides may be important in controlling the synthesis and/or release of respiratory glycoproteins.