The nasal mucosal late allergic reaction to grass pollen involves type 2 inflammation (IL-5 and IL-13), the inflammasome (IL-1ß), and complement.

Non-invasive mucosal sampling (nasosorption and nasal curettage) was used following nasal allergen challenge with grass pollen in subjects with allergic rhinitis, in order to define the molecular basis of the late allergic reaction (LAR). It was found that the nasal LAR to grass pollen involves parallel changes in pathways of type 2 inflammation (IL-4, IL-5 and IL-13), inflammasome-related (IL-1ß), and complement and circadian-associated genes. A grass pollen nasal spray was given to subjects with hay fever followed by serial sampling, in which cytokines and chemokines were measured in absorbed nasal mucosal lining fluid, and global gene expression (transcriptomics) assessed in nasal mucosal curettage samples. Twelve of 19 subjects responded with elevations in interleukin (IL)-5, IL-13, IL-1ß and MIP-1ß/CCL4 protein levels in the late phase. In addition, in these individuals whole-genome expression profiling showed upregulation of type 2 inflammation involving eosinophils and IL-4, IL-5 and IL-13; neutrophil recruitment with IL-1α and IL-1ß; the alternative pathway of complement (factor P and C5aR); and prominent effects on circadian-associated transcription regulators. Baseline IL-33 mRNA strongly correlated with these late-phase responses, whereas a single oral dose of prednisone dose-dependently reversed most nasal allergen challenge-induced cytokine and transcript responses. This study shows that the LAR to grass pollen involves a range of inflammatory pathways and suggests potential new biomarkers and therapeutic targets. Furthermore, the marked variation in mucosal inflammatory events between different patients suggests that in the future precision mucosal sampling may enable rational specific therapy.

Rofecoxib, a COX-2 inhibitor, does not inhibit human gastric mucosal prostaglandin production.

BACKGROUND & AIMS: Rofecoxib, an inhibitor of the inducible cyclooxygenase (COX)-2 enzyme, appears not to cause acute gastroduodenal injury or chronic ulceration. To attribute this to COX-2 selectivity with sparing of gastric mucosal prostaglandin synthesis requires direct proof. METHODS: Twenty-four healthy, nonsmoking Helicobacter pylori-negative volunteers were randomized to 1 of 2 separate concurrent blinded crossover studies. Sixteen volunteers received rofecoxib, 50 mg once daily, for 5 days in one treatment period and placebo in the other. Eight volunteers similarly received naproxen, 500 mg twice daily, and placebo. On day 5 of each period, antral mucosal prostaglandin E2 (PGE2) synthesis was measured by radioimmunoassay after vortexing for 3 minutes. Whole blood COX-1 activity was measured as serum thromboxane (TXB)2- and COX-2 activity as lipopolysaccharide (LPS)-induced PGE2. RESULTS: Naproxen decreased gastric mucosal PGE2 synthesis by 65% (90% confidence interval [CI], 53%-74%; P = 0.001 vs. placebo) in contrast to an 18% increase after rofecoxib (90% CI, -11% to 57%; P = 0.313 vs. placebo). Naproxen also significantly inhibited both serum TXB2 by 94% and LPS-induced PGE2 production by 77% (both P < or = 0.002 vs. placebo), but rofecoxib only inhibited COX-2-dependent LPS-induced PGE(2) (by 79%; P < 0.001 vs. placebo). CONCLUSIONS: Rofecoxib (50 mg) lacked naproxen's ability to reduce the availability of gastroprotective prostaglandins.

Cardiovascular and hypothalamic-pituitary-adrenal axis development in late gestation fetal sheep and young lambs following modest maternal nutrient restriction in early gestation.

The effect of a 15% reduction in maternal nutrition for the first 70 days of gestation on cardiovascular and hypothalamic-pituitary-adrenal (HPA) axis responses to administration of corticotropin releasing hormone (CRH) + arginine vasopressin (AVP) was studied at 128 +/- 0.7 days gestation in fetal sheep and postnatally, at 85 +/- 4.5 days in young lambs. The effect on the fetal cardiovascular response to acute hypoxaemia was also examined. Under basal conditions, fetal heart rate (FHR) was reduced (P < 0.05) and basal femoral artery vascular resistance (FVR) was increased (P < 0.05) in fetuses of dietary-restricted (R) ewes compared with controls (C). Fetal mean arterial pressure (MAP) was similar in both groups. Femoral artery vascular resistance was also greater during hypoxaemia in R fetuses compared with C fetuses (P < 0.05), suggesting that chemoreflex mechanisms were augmented in the R group. The fetal ACTH response to CRH + AVP was similar in both groups. However, cortisol responses to CRH + AVP were smaller in R fetuses compared with C fetuses (P<0.05). Postnatally, basal MAP (P < 0.05), and ACTH (P < 0.01) and cortisol (P < 0.001) responses were greater in R lambs compared with C lambs. It was concluded that modest maternal undernutrition during pregnancy alters development of the cardiovascular system, producing elevated blood pressure in postnatal life. Development of the HPA axis is also altered, with reduced activity during fetal life, but increased activity postnatally. The data suggest that the HPA axis may play a role in mediating the elevation of MAP in R lambs.

Development of carotid chemoreceptor dynamic and steady-state sensitivity to CO2 in the newborn lamb.

1. The maturation of carotid chemoreceptor steady-state and dynamic responses to CO2 in newborn lambs was measured. In total, sixteen fibres (13 lambs) were studied at 3-4 days, nineteen fibres (13 lambs) at 5-9 days and twenty-one fibres (17 lambs) at 10-24 days after birth. 2. Steady-state CO2 sensitivity was measured over a range of arterial CO2 pressures (Pa,CO2) at four levels of arterial O2 pressure (Pa,O2): hyperoxia (Hyp), 115-150 mmHg; normoxia (Nx), 90-105 mmHg; moderate hypoxia (ModHx), 40-60 mmHg; and severe hypoxia (SvHx), 20-35 mmHg. 3. Steady-state CO2 sensitivity was present at all ages, and a significant effect of age (P < 0.001) and Pa,O2 (P < 0.025) (ANOVA) was observed. Older lambs were unable to sustain an increase in chemoreceptor discharge during SvHx as CO2 was increased. 4. Dynamic CO2 sensitivity was measured by producing alternations in end-tidal CO2 levels (etCO2) (alternation amplitude, 1.23 +/- 0.07% (mean +/- S.E.M.); etCO2, 7.56 +/- 0.15%) over 2-8 s at two Pa,O2 levels only: 80-100 (Nx) and 40-60 mmHg (ModHx). Peak and trough values of the oscillation in chemoreceptor discharge were plotted against maximum and minimum etCO2 for the control and CO2-loaded breaths. Dynamic CO2 sensitivity was calculated as the slope between these points. 5. Dynamic CO2 sensitivity was greater than steady-state sensitivity in Nx (P < 0.05) and ModHx (P < 0.01, Student's paired t test). Unlike steady-state CO2 sensitivity, there was no significant effect of age or Pa,O2 on dynamic sensitivity (P > 0.39 and P > 0.68, respectively, ANOVA). 6. Our results show that the neonatal lamb possesses a carotid body steady-state CO2 sensitivity within a few days of birth, an age when hypoxia sensitivity is low. This CO2 sensitivity increases with age, perhaps due to the increasing interaction between CO2 and O2. Dynamic sensitivity of the carotid body to CO2 is mature at birth and does not increase with age, as predicted if the response of the carotid body to rapid changes in CO2 is independent of the sensitivity to the partial pressure of O2 (PO2).

Modulation by "central" PCO2 of the response to carotid body stimulation in man.

We describe a method to assess the effects of PCO2, around and below eucapnia, on the neuromuscular ventilatory response to a standard peripheral chemoreceptor stimulus. Subjects were "passively" hyperventilated (without respiratory muscle activity), at a constant level of ventilation. Stimuli (3-7 breaths N2) were delivered over a range of steady-state PETCO2 (25-43 mmHg). Stimuli during hypocapnia were coupled with a transient increase in FICO2 so that the stimulus to the peripheral chemoreceptors was always "hypoxia at eucapnia". Responses to the stimuli (quantified from the reduction in peak inflation pressure and the magnitude of the evoked diaphragm electromyographic activity) decreased in a graded manner as steady-state PETCO2 fell, disappearing at 7.5 mmHg below eucapnia. Carotid body chemoreceptor recordings from two anaesthetised cats, indicated that the peak firing rate during such stimuli was independent of steady-state PETCO2. The results suggest that the central sensitivity to a peripheral chemoreceptor input may be modulated by changes in steady-state PCO2 around eucapnia and during mild hypocapnia.

Absence of ventilatory responses to alternating breaths of mild hypoxia and air in infants who have had bronchopulmonary dysplasia: implications for the risk of sudden infant death.

Infants who have had bronchopulmonary dysplasia (BPD) are at an increased risk of sudden infant death syndrome. Because failure of the cardiorespiratory response to hypoxia is suggested to play a key role in sudden infant death syndrome, we tested the hypothesis that infants who have had BPD have a reduced respiratory chemoreflex response to hypoxia. We examined the reflex respiratory responses to breath-by-breath alternations in fractional inspired oxygen concentration in eight infants who had had BPD (mean gestation = 27 wk, mean postnatal age = 93 d) who were no longer on supplemental oxygen and compared the responses with those of 12 preterm infants who had not required supplemental oxygen or been mechanically ventilated since birth (mean gestation = 30 wk, mean postnatal age = 38 d). For test runs we alternated fractional inspired oxygen concentration through two gas delivery lines between 0.21 and 0.16 on a breath-by-breath basis, and for control runs we alternated the inspirate between the two gas lines with a fractional inspired oxygen concentration of 0.21 in each. Respiration was measured using inductance plethysmography infants with BPD showed no significant differences between test and control responses for any respiratory variable. In contrast, all respiratory variables in the preterm infants showed test responses significantly greater than control. We speculate that the "blunted" chemoreflex respiratory response seen in infants with BPD may predispose them to subsequent respiratory failure, but we do not known which component of the chemoreflex is impaired.

The respiratory response of healthy term infants to breath-by-breath alternations in inspired oxygen at two postnatal ages.

We have studied the reflex respiratory responses to breath-by-breath alternations in fractional inspired oxygen in a group of healthy term infants at two ages, 43 +/- 7 h (study 1) and 47 +/- 3 d (study 2). Respiration was measured noninvasively using inductance plethysmography. Responses to alternations of fractional inspired oxygen between 0.16 and 0.21 (test runs) were compared with responses to alternating the inspired gas between two lines each containing a fractional inspired oxygen concentration of 0.21 (control runs). The respiratory response was measured as the mean percentage breath-by-breath alternation for inspiratory tidal volume (VTI), expiratory tidal volume (VTE), inspiratory time (TI), expiratory time (TE), frequency (f), mean inspiratory flow (VTI/TI), mean expiratory flow (VTE/TE), timing (TI.f), and ventilation. A significant chemoreflex response was present in the infants at the time of study 1, as shown by test runs that were significantly different from control for TI, TE, f, mean inspiratory flow, mean expiratory flow, timing, and ventilation (p < 0.05), and at study 2 for VTI, VTE, TE, f, mean inspiratory flow, mean expiratory flow, timing, and ventilation (p < 0.05). When control and test runs were compared separately with respect to age, there were no significant differences for any respiratory variable between study 1 and study 2. Thus, we did not observe significant maturation of respiratory chemoreflex responses to hypoxia after an age at which we could detect an established response, and this suggests that the "resetting" of chemoreceptor responses to hypoxia is essentially complete within approximately 24-48 h of birth in humans.