Effect of histamine and methacholine on nasal airway resistance in atopic and nonatopic subjects: Comparison with bronchial challenge and skin test responses

Serial nasal, intracutaneous, or bronchial challenges were carried out with solutions containing 2- or 3-fold increments in histamine (H) or methacholine (Meth) concentration until nasal airway resistance (NAR) increased by more than 100%, a large intracutaneous reaction was elicited, or FEV₁ decreased by 20% or more. Thirty nonatopic and 48 asymptomatic atopic subjects were studied, the latter group divided into rhinitic patients with and without asthma. Several types of data analysis demonstrated there was no significant difference in the nasal or cutaneous effects of H or Meth between the atopic and nonatopic groups. Comparable results were obtained in a subgroup of 39 subjects (13 normal, 13 atopic, and 13 atopic with asthma) who underwent all six test sequences (i.e., nasal, cutaneous, and bronchial with both drugs). As expected, the asthmatics showed significantly increased bronchial reactivity to both agents. In comparison with Meth, H had a much greater effect on the nasal mucosa and skin than on the bronchi. It is concluded that, contrary to bronchial responses, but in accord with cutaneous reactivity, the nasal responses of nonatopic subjects, atopic persons with allergic rhinitis alone, and subjects with both allergic rhinitis and asthma show no intergroup differences on testing with H or Meth.     

Effect of theophylline on cortisol secretion

Theophylline is thought to improve asthma by increasing intracellular cyclic adenosine 3'-5'-monophosphate (cAMP) levels. It has been demonstrated in experimental animals that elevation of intracellular cAMP in the adrenal cortex causes an increased secretion of cortisol. We studied whether therapeutic doses of theophylline given intravenously and orally to human subjects over 3 days would increase cortisol secretion. A single-blind, 6-day protocol was employed in five normal and five asthmatic volunteers. Adrenal function was monitored by 8 A.M. and 4 P.M. serum cortisol and adrenocorticotropic hormone (ACTH) levels; daily 24-hr urine for urinary-free cortisol (UFF), 17-hydroxysteroids (17-OH), and 17-ketosteroids (17-KS); and alternate-day cortisol secretory rates (FSR) measured by isotope dilution after intravenous 14C-cortisol. Serum theophylline concentration also was monitored. Results in normal and asthmatic subjects were similar. Theophylline caused a significant but transient increase in UFF and 17-OH excretion. Urine volumes also increased significantly, suggesting that the renal effect of theophylline accounted for the increased UFF and 17-OH excretion. FSR increased during the first 24 hr after theophylline in eight of nine cases (p < 0.05 by sign test), mean values increasing from 14.2 to 19.3 mg, but this effect had dissipated by day 3 of theophylline administration. In contrast to these findings, theophylline had no effect on serum cortisol or ACTH or urinary 17-KS. It is likely that serum cortisol and ACTH remained unchanged because the increase in cortisol secretion was offset by a concomitant increase in cortisol clearance. It is concluded that theophylline produces a small, transient increase in cortisol secretion and clearance, and this effect is similar in asthmatic and normal subjects.     

Activation of the complement system by radiographic contrast media: studies in vivo and in vitro.

The effect of radiographic contrast media (RCM) on the complement system was studied in vivo and in vitro. In 65 patients undergoing intravenous pyelography, plasma was obtained before and 3, 5, 10, 20, 30, and 60 min postinfusion. Nine patients experienced immediate generalized reactions (IGR) post-RCM infusions. Six patients developed urticaria, 1 developed angioedema, and 2 developed nausea and hypotension. A significant decrease in CH50 occurred in 29 patients, including 6 with IGR. Split products of C3 were detected in 24 of these patients. Six patients without change in CH50 had detectable C3 split products. There was a statistically significant decrease in hemolytically active C3 and factor B, but not C1q or C4 in the group with decreased CH50 when compared to the group without CH50 change. All patients had normal levels of C1 esterase inhibitor, C3aI (serum carboxypeptidase B), C3bI, and βIH. Neither anti-RCM antibodies nor immune complexes were detected in any patient's plasma. In vitro, decreased CH50 and hemolytically active C4, C3, properdin, and factor B were found with incubation of plasma with RCM. These changes occurred independent of the buffer used (EDTA/EGTA). Finally, C3 split products were detected in the reaction mixtures. These data indicate that RCM is associated with decreased hemolytic complement activity, both in vivo and in vitro. Furthermore, the in vitro changes occurred without the presence of calcium or magnesium, indicating that complement activation by RCM may occur in a nonsequential manner.     

Spatial Distribution of Mast Cells Regulates Asymmetrical Angiogenesis at the Ocular Surface

Mast cells, historically known for their function as effector cells in the induction of allergic diseases, reside in all vascularized tissues of the body, particularly, in proximity to blood and lymphatic vessels. Despite being neighboring sentinel cells to blood vessels, whether the spatial distribution of mast cells regulates the degree of angiogenesis remains to be investigated. Herein, an asymmetrical distribution of mast cells was shown at the murine ocular surface, with the higher number of mast cells distributed along the nasal limbus of the cornea compared with the temporal side. Using a well-characterized murine model of suture-induced corneal neovascularization, insult to the nasal side was shown to result in more extensive angiogenesis compared with that to the temporal side. To directly assess the impact of the spatial distribution of mast cell on angiogenesis, neovascularization was induced in mast cell–deficient mice (cKit^w-sh). Unlike the wild-type (C57BL/6) mice, cKit^w-sh mice did not show disproportionate growth of corneal blood vessels following the temporal and nasal insult. Moreover, cromolyn-mediated pharmacologic blockade of mast cells at the ocular surface attenuated the asymmetrical nasal and temporal neovascularization, suggesting that spatial distribution of mast cells significantly contributes to angiogenic response at the ocular surface.

A transparent cornea, devoid of any blood vessels, is essential to maintaining visual acuity.^1,2 Corneal neovascularization, characterized by abnormal new blood vessel growth from preexisting limbal vessel structures, occurs in various corneal pathologies, including inflammatory disorders, trauma, and corneal graft rejection.^3,4 Pathologic insults lead to a disruption of the equilibrium of pro-angiogenic and anti-angiogenic factors, resulting in proliferation and migration of vascular endothelial cells to form new blood vessels.⁵ Interestingly, the pathologic growth of blood vessels is not always evenly distributed throughout the cornea. Ocular surface conditions, including peripheral hypertrophic subepithelial corneal opacification and pterygium, characterized by pathologic angiogenesis, have long been clinically observed to predominantly affect the nasal side of the cornea.6, 7, 8 Despite such observations, the underlying mechanism that may contribute to the uneven distribution of neovascularization in tissues, such as the cornea, is yet to be uncovered.Mast cells, the tissue-resident cells, are present throughout vascularized tissues in the body, especially in abundance around the blood and lymph vessels.^9,10 At the ocular surface, mast cells are distributed in the peripheral cornea, limbus, and conjunctiva.^11,12 On activation, mast cells degranulate and release preformed and newly synthesized inflammatory mediators into the microenvironment.¹⁰ Granules are composed of various growth factors, cytokines, amines, and enzymes such as tryptase and β-hexosaminidase.^9,13 The role of mast cells in ocular allergy is well established, and the use of a mast cell inhibitor, cromolyn sodium, to manage allergic symptoms, is a common practice in the clinic. Apart from their well-established role in allergy, mast cells also regulate innate and adaptive immune responses and angiogenesis.^14,15Ocular surface mast cells promote corneal neovascularization, in part, by secreting high levels of vascular endothelial growth factor-A.¹⁶ In the current study, a series of experiments were conducted to investigate whether mast cells contribute to the observed asymmetry in vessel growth between the nasal and temporal side of the cornea. Specifically, the effect of the spatial distribution of mast cells were investigated on pathologic vessel formation using a well-characterized murine model of inflammatory corneal neovascularization and genetically modified mast cell–deficient cKit^w-sh mice. Herein, suture placement on the nasal side resulted in more extensive corneal neovascularization compared with that on the temporal side. Moreover, a higher number of mast cells were observed on the nasal half of the cornea compared with the temporal half. However, mast cell deficiency and pharmacologic blockade of mast cell activation abrogated the difference in the degree of angiogenesis following nasal and temporal insult, suggesting a critical contribution of mast cells in promoting disproportionate angiogenic response at the ocular surface.