Octreotide does not alter endotoxin lethality in mice or endotoxin-induced suppression of human leukocyte migration.

Octreotide, a somatostatin analog, was evaluated for its effects on long-term survival in a mouse model of endotoxemia and for its effects on endotoxin-induced suppression of human leukocyte migration. Swiss Webster mice were simultaneously rendered endotoxemic with a single intraperitoneal injection of 800 micrograms E. coli Lipopolysaccharide (LPS) and treated with one of four doses of subcutaneous (s.c.) octreotide (1.0 mg/kg in 0.4 ml saline, 0.1 mg/kg in 0.4 ml saline, 0.1 mg/kg in 0.04 ml saline, or 0.001 mg/kg in 0.04 ml saline) or saline alone (fluid-resuscitated control group: 0.4 ml saline s.c.; or non-fluid-resuscitated control group: 0.04 ml saline s.c.). Octreotide was continued with or without supplemental s.c. fluid resuscitation (0.4 ml saline) at eight hour intervals for either twenty-four or forty hours. There was no statistical significance to differences in long-term survival between comparable groups of octreotide treated vs saline treated animals during the entire fourteen day period of observation. Fluid resuscitation during the first forty hours following endotoxemia induction delayed death, but did not significantly improve long-term survival. In vitro work was conducted to determine the effect of octreotide on endotoxin-induced suppression of human leukocyte migration. Octreotide at concentrations ranging from 3.05 x 10(-5) Molar to 3.05 x 10(-11) Molar had no significant effect on leukocyte migration. In this study octreotide treatment failed to improve long-term survival in mice with endotoxemia and did not alter endotoxin-induced suppression of leukocyte migration.

The effect of body position on the respiratory rate of infants with tachypnea.

In neonatal disease states where lung compliance is reduced (e.g., inadequate resorption of fetal lung fluid or, surfactant deficiency) an infant's normally low functional residual capacity (FRC) decreases even further. Tachypnea is an efficient compensatory maneuver for the newborn. We evaluated the effect of different bed and body positions on the increased respiratory rate observed in infants with transient tachypnea of the newborn (TTN), infant respiratory distress syndrome (RDS), and bronchopulmonary dysplasia (BPD). Seventeen infants were studied (TTN, n = 6; RDS, n = 6; BPD, n = 5) in four different positions: supine flat, supine elevated, prone flat, and prone elevated. Respiratory rate and heart rate were evaluated in each position. Analysis of variance for the three patient groups showed a lower respiratory rate when the bed was elevated 20-30 degrees compared to flat (P = 0.0001), in the prone posture compared to supine (P = 0.031), and no significant difference in heart rate. The lowest mean respiratory rate occurred when patients were in the prone elevated position. The significant improvement in tachypnea seen in the prone and elevated positions was likely related to improved FRC resulting from reduced cephalad stress on the diaphragm from the abdomen. Positioning neonatal patients with respiratory insufficiency was a simple and safe therapeutic maneuver with prompt and demonstrable benefit.

Neonatal lung neutrophils and elastase/proteinase inhibitor imbalance.

Serial bronchoalveolar lavage (BAL) was performed prospectively on 10 normal control subjects, 20 Respiratory Distress Syndrome (RDS), and 11 Bronchopulmonary Dysplasia (BPD) newborn infants to evaluate the role of pulmonary inflammation in neonatal lung disease. Minimal inflammation was found in BAL at less than 24 h of life in all groups, but significant pulmonary polymorphonuclear leukocyte (PMN) influxes were noted at 96 h in RDS and BPD compared with control subjects. By 1 wk of life, BAL PMN counts returned to normal in RDS, but counts remained significantly elevated through 5 wk in BPD. Alveolar macrophage (AM) counts were significantly elevated at 96 h in RDS (p less than 0.05), but were significantly depressed in BPD at 4 and 5 wk (p less than 0.05). The BAL elastase/alpha 1-proteinase inhibitor (alpha 1Pi) ratios in RDS did not differ from those of normal control subjects; however, these ratios were significantly elevated from 1 through 4 wk of life in BPD, placing these infants at risk for proteolytic lung damage. Lavage elastase levels were elevated in both RDS and BPD, associated with a parallel increase in BAL alpha 1Pi in RDS and depressed BAL alpha 1Pi in BPD. These findings suggest that pulmonary inflammation, associated with a prolonged PMN influx and an imbalance between elastase and alpha 1Pi, may contribute to the development of the neonatal chronic lung disease, BPD.

Histamine regulates lymphocyte mitogenic responses through activation of specific H1 and H2 histamine receptors.

In previous studies we have reported that patients with mild atopic eczema have enhanced lymphocyte mitogenesis while those with severe disease have markedly suppressed responses. Similarly, histamine in low concentrations enhanced mitogenesis while higher levels inhibit mitogen stimulated thymidine uptake. In the present study, we investigated the kinetics of this response and the interaction of histamine with its cell-surface receptors on lymphocytes. Histamine (10(-3) M) markedly inhibited [3H]-thymidine incorporation to 27% of control levels when added at the beginning of a 72 h culture period. When added after 24 and 48 h of culture, however, the suppression was much less (62 and 88% of control). Lymphocyte cultures pulsed for 1 h with histamine, washed free of the agent and then cultured with mitogen also showed marked suppression of [3H]-thymidine uptake. The kinetics of the response suggest that histamine acts to inhibit initial processing or recruitment steps in the mitogenic assay. Cimetidine, an H2-receptor blocking agent, prevented the suppressive effect of high levels of histamine while diphenhydramine, an H1 blocker, abolished the enhancement observed with low levels. Pre-incubation of mononuclear cell suspensions, which has been shown to decrease suppressor activity, resulted in a decreased response to added histamine. This change in histamine responsiveness was associated with an alteration in H1:H2 histamine binding as determined with a radiolabelled ligand-binding assay. Histamine suppression of mitogenesis was associated with an increase in cellular cAMP levels while enhancement was accompanied by a small increase in cGMP. These data suggest that lymphocyte function may be regulated, in part, by histamine receptor bearing cells with H1 stimulation having a role in enhancement of mitogenesis and H2 stimulation resulting in normal suppressor activity.

Inflammatory and immune cell function in psoriasis: II. Monocyte function, lymphokine production.

We have previously confirmed that subjects with psoriasis have an alteration of cell-mediated immune responses. We now report a possible in vitro corollary; the amount of lymphokine (lymphocyte-derived chemotactic factor) released by both antigen-stimulated and control lymphocytes is decreased in psoriatic subjects; 61% of similar values for normal subjects. Monocyte migration to complement-derived chemotactic factors is reported to directly correlate to skin tests; however, in psoriasis the relation is inverse, i.e., a 200% increase in complement factors and 136% increase to lymphocyte-derived chemotactic factor in monocyte migration is noted in psoriatic subjects when compared with normal subjects. This increased migration does not correlate with amount of disease and is still present in "disease-free" subjects. Culturing monocytes from psoriatic subjects in media alone demonstrates they reduce more (205%) nitroblue tetrazolium than do monocytes of normal subjects. These data demonstrate that monocytes from subjects with psoriasis are altered and suggest an apparent inherent metabolic disorder.

In vitro quantitation of cell-mediated immunity in guinea-pigs by macrophage reduction of nitro-blue tetrazolium.

In the cell-mediated immune (CMI) system lymphocytes from sensitized animals incubated with antigen manufacture and release lymphokines which activate the hexose-monophosphate shunt in macrophages. The rate-limiting enzyme of this activation is NADPH oxidase, the activity of which can be quantitated by the amount of nitro-blue tetrazolium reduced to formazan, a blue precipitate. Data is presented which demonstrates that lymphokine-activated macrophages can be microscopically quantitated, both in the direct and indirect assays, by counting the number of macrophages containing formazan precipitate. The indirect component of this assay correlates directly to the skin test diameter. Further, it correlates better to the skin test than another assay for CMI, the macrophages aggregation factor assay. The simplicity and reproducibility of this assay provides another method whereby lymphokine activation of physiological events in macrophages can be determined.