Airways are richly innervated by 4 nervous systems: adrenergic, cholinergic, inhibitory nonadrenergic noncholinergic (i-NANC), and excitatory NANC (e-NANC) nervous systems. Dysfunction or hyperfunction of these systems may be involved in the inflammation or airway hyperresponsiveness observed in asthmatic patients. The cholinergic nervous system is the predominant neural bronchoconstrictor pathway in humans. Airway inflammation results in exaggerated acetylcholine release from cholinergic nerves via dysfunction of the autoreceptor, muscarinic M2, which is possibly caused by a major basic protein or IgE. Vasoactive intestinal peptide (VIP) and nitric oxide (NO) released from i-NANC nerves act as an airway smooth muscle dilator. The effects of VIP and NO are diminished after allergic reaction by inflammatory cell-mediated tryptase and reactive oxygen species. Thus, in asthmatic airways, the inflammatory change-mediated neural imbalance may result in airway hyperresponsiveness. Tachykinins derived from e-NANC nerves have a variety of actions including airway smooth muscle contraction, mucus secretion, vascular leakage, and neutrophil attachment; and they may be involved in the pathogenesis of asthma. Since tachykinin receptor antagonists are effective for bradykinin- and exercise-inducedbronchoconstriction in asthmatic patients, these drugs may be useful for asthma therapy.
In the lung, there is increasing evidence that endogenous nitric oxide (NO) plays multiple roles in physiological control of airway functions, immune responses and host defense against infection, and it is also implicated in inflammatory disease of the airways. As elsewhere, it is generally accepted that NO derived from constitutive NO synthase (cNOS) is involved in physiological regulation of airway function, whereas NO derived from inducible NO synthase (iNOS) is involved in immune responses and inflammatory diseases of the airway. In this mini review, first we describe evidence showing the possible roles of NO and NO-related compounds in nonadrenergic noncholinergic (NANC) relaxation and inhibitory action on excitatory neuro-effector transmission, thereby indicating that NO derived from neuronal cNOS plays a role to provide “double braking” in bronchoconstrictions. Secondly, we will discuss the possible involvement of epithelial damage due to excessive NO production through iNOS in the genesis of airway hyperreactivity and airway inflammation.
While it is clear that the clinical expression of IgE-mediated diseases depends upon the actions of multiple mediators, histamine, the earliest recognized mediator of allergy, remains a prominent contributor. Histamine released from mast cells binds to specific receptors (H1, H2, H3) to produce its clinical effects. The cardinal features of asthma include smooth muscle spasm, mucosal edema, inflammation and mucus secretion. It has been demonstrated that two of these features, bronchospasm and mucosal edema, can be caused by H1-receptor stimulation, while H2- and possibly H1-activation are probably minor causes of mucus secretion. Histamine interacts directly with the endothelial cells (EC) and induces permeability, a transient expression of P-selectin and the secretion of lipid mediators (e.g. PGI2, PAF and LTB4). Moreover, histamine induces a significant increase of IL-6 and IL-8 secretion by EC. Since IL-8 exerts a chemotactic activity for neutrophils, eosinophils and basophils, and IL-6 is involved in endothelium permeability, the secretion of cytokines may be involved in the late phase reaction. Some antihistamines (i.e., levocabastine, terfenadine, loratadine, azelastine and oxatomide) can reduce ICAM-1 expression. The participation of histamine in the allergic inflammation, including asthma, must be re-examined, since the effects of histamine are more widespread.
Peptide-leukotrienes (p-LTs) (LTC4, LTD4 and LTE4) are major metabolites of the arachidonate 5-lipoxygenase pathway. Although a number of papers have reported that p-LTs induce potent bronchial smooth muscle constriction as well as airway mucus secretion, vascular permeability and proliferation of airway smooth muscle cells, it had not been recognized that they are pivotal chemical mediators in asthmatic diseases until recently. Yet, several potent and selective antagonists against p-LTs and inhibitors of p-LT formation revealed that p-LTs play significant roles in not only allergic but non-allergic asthma including exercise and aspirin-induced asthma. In addition, it has been reported that p-LTs participate in rhinitis, especially nasal blockage. In this article, recent development of drugs relating to p-LTs and their therapeutic effects for asthma are mainly reviewed.
Bronchial asthma is considered to be a chronic airway inflammatory disease influenced by genetics and environmental factors. Airway hyperresponsiveness (AHR) is a characteristic of the disease generally associated with airway inflammation. Recently, the potential targets for therapeutic intervention in AHR has focused on the inhibition or antagonism of lipid mediators including leukotrienes, thromboxanes and platelet-activating factor. Furthermore, the inhibition of Th2 cytokines, such as interleukin-4 or interleukin-5, is another target for the prevention of AHR. In the present review, we describe the role of cytokines and arachidonic acid metabolites in the onset and development of AHR.
Airway hyperreactivity (AHR) is an important characteristic feature of asthma. Recently, it has been recognized that airway inflammation underlies the phenomenon of AHR. Kinins such as bradykinin (BK) and kallidin (KD) have been implicated as mediators of airway inflammatory diseases. Tachykinins such as substance P (SP) and neurokinin A (NKA) produce a variety of effects on the airways. These effects include changes in bronchomotor tone, vasodilatation, increase in vascular permeability and facilitation of the release of other transmitters. Non-cholinergic responses are due to release of neuropeptides such as tachykinins from sensory nerve endings. Kinins and tachykinins have been implicated in neurogenic inflammation. The O3 exposure (3 ppm, 30 min) induced AHR to ACh in guinea pigs. The O3-induced AHR was significantly enhanced by pretreatment with captopril, a kininase II inhibitor. Infusion of subthreshold dose of BK and KD developed AHR to ACh. The O3-induced AHR was significantly inhibited by pretreatment with capsaicin. Infusion of the subthreshold dose of SP and NKA developed an AHR to ACh. The KD-induced AHR was inhibited by pretreatment with capsaicin. Kinins and tachykinins may be therefore involved in the O3-induced AHR, and kinins may act through tachykinin intervention on the O3-induced AHR.
Nonspecific airway hyperresponsiveness (AHR) is a common feature of allergic bronchial asthmatics, but the underlying mechanisms of AHR have yet to be elucidated. The importance of AHR in the pathogenesis of asthma has been suggested by its relevance to the severity of this disease. There is thus a need to understand the underlying mechanisms of AHR for the sake of asthma therapy. In allergic asthmatics, airway smooth muscles (ASMs) obtained from in vivo hyperresponsive patients have in vitro hyperresponsiveness to cholinergic agonists. It is therefore possible that the mechanisms responsible for the AHR exist, at least in part, on the ASM site. Although ASM is known to contract in response to acetylcholine via muscarinic M3 receptors and this contractile response is augmented during AHR, no alteration in muscarinic receptor density in ASM has been demonstrated in various AHR models. It is thus likely that augmented intracellular signaling might be a possible reason for the AHR. In fact, recent investigations demonstrated increases in the levels of GTP binding protein, Ca2+ mobilization and inositol 1, 4, 5-trisphosphate generation and so on in hyperresponsive ASM.
Mucociliary transport function can be determined by ciliary motility of airway epithelial cells, the amount and physicochemical properties of airway surface fluid, and the airway integrity. Mucus glycoprotein is released from submucosal glands and goblet cells in response to a variety of stimuli and, on other hand, water is secreted by airway epithelial cells through the movement of electrolytes. Marked airway goblet cell hyperplasia has been found in patients who died of severe asthma, indicating that goblet cell hypersecretion may play a significant role in the formation of mucus plugs in the respiratory tract. Goblet cell secretion is regulated by autonomic nerves and various chemical mediators associated with asthma. Antigen challenge causes an increase in mucus discharge from goblet cells in ovalbuminsensitized animals, and this effect can be greatly inhibited by an histamine H2-receptor antagonist. Similarly, histamine released by antigen challenge stimulates airway epithelial Cl secretion and, hence, water secretion toward the airway lumen. There is ample evidence that mucociliary clearance is impaired in patients with asthma, which results in deterioration of airflow limitation. The precise mechanism for this impairment remains uncertain, but bronchospasm and the increased mucus secretion induced by peptide leukotrienes may be involved.