inositol-1-4-5-trisphosphate and Asthma

In the first part of this series of papers (Székely and Pataki, 102) the pathogenesis of asthma was approached as a pathological antigen-antibody complex induced vago-vagal axon reflex. In the next part (103) the contribution of individual hormonal predisposition, the environmental and the most frequent allergizing factors have been reviewed. In the first section of this last (third) part of the review the genetic factors contributing to the asthma are surveyed. In this field a great progress has been made during the last decade, a lot of genes have been pinpointed which contribute to the heredity of the disease. In the second section of this last paper on the etiology of asthma an attempt is made to summarize the previously reviewed data and some new ones. Actually a new hypothesis is proposed that beyond the multitude of genetic, environmental and hormonal factors the underlying biochemical mechanism is simple: the disequilibrium of two functionally opposing second messenger systems in the airways: the Ca i ++ liberating PLC-PKC cascade and the Ca i ++ level reducing cAMP mediated one with preponderance of the former.

Topics: Animals; Asthma; Bronchoconstriction; Calcium Signaling; Cyclic AMP; Environment; Genetic Predisposition to Disease; Humans; Inositol 1,4,5-Trisphosphate; Pedigree; Protein Kinase C; Reflex, Abnormal; Risk Factors; Second Messenger Systems; Type C Phospholipases

The house dust mite is the principal source of perennial aeroallergens in man. How these allergens activate innate and adaptive immunity is unclear, and therefore, there are no therapies targeting mite allergens. Here, we show that house dust mite extract activates store-operated Ca

Topics: Animals; Antigens, Dermatophagoides; Arthropod Proteins; Asthma; Calcium Signaling; Cell Movement; HEK293 Cells; Humans; Inhalation Exposure; Inositol 1,4,5-Trisphosphate; Ion Channel Gating; Jurkat Cells; Mast Cells; Mice, Inbred C57BL; Nasal Mucosa; Neoplasm Proteins; ORAI1 Protein; Pyroglyphidae; Receptor, PAR-2; Receptors, G-Protein-Coupled; Receptors, Thrombin; Serine Endopeptidases; Stromal Interaction Molecule 1

Enhanced contractility of airway smooth muscle (ASM) is a major pathophysiological characteristic of asthma. Expanding the therapeutic armamentarium beyond β-agonists that target ASM hypercontractility would substantially improve treatment options. Recent studies have identified naturally occurring phytochemicals as candidates for acute ASM relaxation. Several flavonoids were evaluated for their ability to acutely relax human and murine ASM ex vivo and murine airways in vivo and were evaluated for their ability to inhibit procontractile signaling pathways in human ASM (hASM) cells. Two members of the flavonol subfamily, galangin and fisetin, significantly relaxed acetylcholine-precontracted murine tracheal rings ex vivo (n = 4 and n = 5, respectively, P < 0.001). Galangin and fisetin also relaxed acetylcholine-precontracted hASM strips ex vivo (n = 6-8, P < 0.001). Functional respiratory in vivo murine studies demonstrated that inhaled galangin attenuated the increase in lung resistance induced by inhaled methacholine (n = 6, P < 0.01). Both flavonols, galangin and fisetin, significantly inhibited purified phosphodiesterase-4 (PDE4) (n = 7, P < 0.05; n = 7, P < 0.05, respectively), and PLCβ enzymes (n = 6, P < 0.001 and n = 6, P < 0.001, respectively) attenuated procontractile Gq agonists' increase in intracellular calcium (n = 11, P < 0.001), acetylcholine-induced increases in inositol phosphates, and CPI-17 phosphorylation (n = 9, P < 0.01) in hASM cells. The prorelaxant effect retained in these structurally similar flavonols provides a novel pharmacological method for dual inhibition of PLCβ and PDE4 and therefore may serve as a potential treatment option for acute ASM constriction.

Topics: Animals; Aorta; Asthma; Bronchoconstriction; Calcium Signaling; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Evaluation, Preclinical; Flavonoids; Flavonols; Humans; Inositol 1,4,5-Trisphosphate; Male; Mice; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Phosphodiesterase 4 Inhibitors; Phospholipase C beta

Asthma is characterized by airway hyper-responsiveness and variable airflow obstruction, in part as a consequence of hyper-contractile airway smooth muscle, which persists in primary cell culture. One potential mechanism for this hyper-contractility is abnormal intracellular Ca(2+) handling.. We sought to compare intracellular Ca(2+) handling in airway smooth muscle cells from subjects with asthma compared to non-asthmatic controls by measuring: i) bradykinin-stimulated changes in inositol 1,4,5-trisphosphate (IP3) accumulation and intracellular Ca(2+) concentration, ii) sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) expression, iii) mechanisms of cytoplasmic Ca(2+) clearance assessed following instantaneous flash photolytic release of Ca(2+) into the cytoplasm.. We found no differences in airway smooth muscle cell basal intracellular Ca(2+) concentrations, bradykinin-stimulated IP3 accumulation or intracellular Ca(2+) responses. Quantification of SERCA2 mRNA or protein expression levels revealed no differences in ASM cells obtained from subjects with asthma compared to non-asthmatic controls. We did not identify differences in intracellular calcium kinetics assessed by flash photolysis and calcium uncaging independent of agonist-activation with or without SERCA inhibition. However, we did observe some correlations in subjects with asthma between lung function and the different cellular measurements of intracellular Ca(2+) handling, with poorer lung function related to increased rate of recovery following flash photolytic elevation of cytoplasmic Ca(2+) concentration.. Taken together, the experimental results reported in this study do not demonstrate major fundamental differences in Ca(2+) handling between airway smooth muscle cells from non-asthmatic and asthmatic subjects. Therefore, increased contraction of airway smooth muscle cells derived from asthmatic subjects cannot be fully explained by altered Ca(2+) homeostasis.

Topics: Adult; Asthma; Bradykinin; Bronchi; Calcium; Case-Control Studies; Female; Humans; Inositol 1,4,5-Trisphosphate; Male; Middle Aged; Muscle Contraction; Myocytes, Smooth Muscle; Photolysis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Vasodilator Agents

The signal transduction pathway for A1 adenosine receptor in airway smooth muscle from allergic rabbits was studied by investigating the effect of the selective A1 adenosine-receptor agonist N6-cyclopentyladenosine (CPA) on tissue levels of inositol 1,4, 5-trisphosphate [Ins(1,4,5)P3] measured by protein binding assay. CPA caused a rapid, transient, and concentration-dependent elevation of Ins(1,4,5)P3 in airways from allergic rabbits. The agonist also produced a concentration-dependent contraction of the airway preparations from these animals. Both the Ins(1,4,5)P3 and contractile responses generated by CPA were attenuated by the phospholipase C (PLC) inhibitor U-73122, indicating the coupling of these responses to PLC. The CPA-induced Ins(1,4,5)P3 production observed in the allergic rabbit tissues was also inhibited by the adenosine-receptor antagonist 8-( p-sulfophenyl)-theophylline, suggesting that the effect was mediated by A1 adenosine receptors. On the other hand, the A2 adenosine-receptor agonist CGS-21680 was ineffective in altering the tissue concentration of Ins(1,4,5)P3, indicating that A2 adenosine receptors may not be involved in the activation of PLC in the allergic rabbit airway smooth muscle. In this preparation, the Gi-Go inhibitor pertussis toxin (PTX) attenuated the CPA-induced Ins(1,4,5)P3 accumulation, providing evidence that the generation of Ins(1,4,5)P3 by A1 adenosine-receptor stimulation is coupled to a PTX-sensitive G protein(s). The results suggest that activation of A1 adenosine receptors in allergic rabbit airway smooth muscle causes the production of Ins(1,4,5)P3 via a PTX-sensitive G protein-coupled PLC, and this signaling mechanism may be involved, at least in part, in the generation of contractile responses. It is hypothesized that this process may contribute to adenosine-induced bronchoconstriction in allergic asthma.

Topics: Adenosine; Airway Resistance; Allergens; Animals; Asthma; Bronchi; Dust; Estrenes; Immunoglobulin E; In Vitro Techniques; Inositol 1,4,5-Trisphosphate; Lung Compliance; Mites; Muscle Contraction; Muscle, Smooth; Phenethylamines; Purinergic P1 Receptor Agonists; Pyrrolidinones; Rabbits; Receptors, Purinergic P1; Respiratory Hypersensitivity

The effects of nebulized platelet-activating factor (PAF) on the pulmonary and cardiovascular systems, and on the platelets present in peripheral blood were investigated in 9 normal individuals and in 6 patients with asthma and 3 individuals with lyso-PAF. The inhalation of PAF caused an acute decrease in specific airway conductance. The circulatory system parameters monitored showed an increase in heart rate while blood pressure decreased in both groups that were studied. The inhalation of PAF led to a significant increase in the differential count of polymorphonuclear leukocytes after 15 min; the count returned to the initial level after 24 h. However, the platelet count remained unchanged. The phosphatidylinositol (PI) turnover and in particular the formation of 1,4,5-inositoltrisphosphate (IP3) in platelets were investigated after PAF inhalation. It also mediated an increase in intracellular free calcium concentration, [Ca2+]i, in response to a second challenge with exogenous PAF. The basal levels of IP3 and [Ca2+]i were significantly greater in the platelets of patients with asthma than in those of normal individuals (p less than 0.01). Platelets that had been isolated from normal and asthmatic subjects had a higher concentration of IP3 and [Ca2+]i in the platelets after an in vitro exposure to PAF. After an inhalation challenge with PAF, the platelets of both the normal individuals and the patients with asthma showed a specific refractoriness to the in vitro exposure to PAF. Perhaps, this is an explanation for the PAF-dependent tachyphylaxis that is commonly observed in both normal and asthmatic individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Administration, Inhalation; Adolescent; Adult; Asthma; Blood Platelets; Bronchoconstriction; Female; Humans; Inositol 1,4,5-Trisphosphate; Male; Phosphatidylinositols; Platelet Activating Factor; Platelet Count