Prostaglandin D₂ (PGD₂), one of the key lipid mediators of allergic airway inflammation, is increased in the airways of asthmatics. However, the role of PGD₂ in the pathogenesis of asthma is not fully understood. In the present study, effects of PGD₂ on smooth muscle contractility of the airways were determined to elucidate its role in the development of airway hyperresponsiveness (AHR). In a murine model of allergic asthma, antigen challenge to the sensitized animals caused a sustained increase in PGD₂ levels in bronchoalveolar lavage (BAL) fluids, indicating that smooth muscle cells of the airways are continually exposed to PGD₂ after the antigen exposure. In bronchial smooth muscles (BSMs) isolated from naive mice, a prolonged incubation with PGD₂ (10⁻⁵ M, for 24 h) induced an augmentation of contraction induced by acetylcholine (ACh): the ACh concentration-response curve was significantly shifted upward by the 24-h incubation with PGD₂. Application of PGD₂ caused phosphorylation of ERK1/2 and p38 in cultured BSM cells: both of the PGD₂-induced events were abolished by laropiprant (a DP₁ receptor antagonist) but not by fevipiprant (a DP₂ receptor antagonist). In addition, the BSM hyperresponsiveness to ACh induced by the 24-h incubation with PGD₂ was significantly inhibited by co-incubation with SB203580 (a p38 inhibitor), whereas U0126 (a ERK1/2 inhibitor) had no effect on it. These findings suggest that prolonged exposure to PGD₂ causes the BSM hyperresponsiveness via the DP₁ receptor-mediated activation of p38. A sustained increase in PGD₂ in the airways might be a cause of the AHR in allergic asthmatics.

Rubratoxin A, a potent inhibitor of PP2A, is known to suppress smooth muscle contraction. The inhibitory role of PP2A in smooth muscle contraction is still unclear. In order to clarify the regulatory mechanisms of PP2A on vascular smooth muscle contractility, we examined the effects of rubratoxin A on the Ca²⁺-induced contraction of β-escin skinned carotid artery preparations from guinea pigs. Rubratoxin A at 1 µM and 10 µM significantly inhibited skinned carotid artery contraction at any Ca²⁺ concentration. The data fitting to the Hill equation in [Ca²⁺]-contraction relationship indicated that rubratoxin A decreased F_max-Ca2+ and increased [Ca²⁺]₅₀, indices of Ca²⁺ sensitivity for the force and myosin-actin interaction, respectively. These results suggest that PP2A inhibition causes downregulation of the myosin light chain phosphorylation and direct interference with myosin-actin interaction.

Endothelin (ET) receptor antagonists: BQ-123 (ET_A), BQ-788 (ET_B), tezosentan (dual ET receptor antagonist) protect against the development of postoperative ileus (POI) evoked by ischemia-reperfusion (I/R). The current experiments explored whether ET antagonists prevent the occurrence of POI evoked by surgical gut manipulation. Intestinal transit was assessed by measuring the rate of dye migration subsequent to skin incision (SI), laparotomy (L), or laparotomy and surgical gut handling (L+M) in diethyl ether anaesthesized rats (E). Experimental animals were randomly sub-divided into two groups depending on the time of recovery following surgery: viz. either 2 or 24 h (early or late phase POI). E and SI did not affect the gastrointestinal (GI) transit. In contrast, L and L+M significantly reduced GI motility in comparison to untreated group (UN). Tezosentan (10 mg/kg), BQ-123 and BQ-788 (1 mg/kg) protected against development of L+M evoked inhibition of intestinal motility in the course of late phase, but not early phase POI. Furthermore, tezosentan alleviated the decrease in the contractile response of the longitudinal jejunal smooth muscle strips to carbachol in vitro induced by L+M. The serum ET(1–21) concentration was not increased in either the early or the late phase POI groups after surgery compared to control animals. This study indicates that delay in the intestinal transit in late phase of surgically induced POI involves an ET-dependent mechanism.

All the cells of rat detrusor muscle fall into one of five ultrastructural types: muscle cells, fibroblasts, axons and glia, and vascular cells (endothelial cells and pericytes). The tissue is ~79% cellular and 21% non-cellular. Muscle cells occupy 72%, nerves ~4% (1/3 axons, 2/3 glia), and fibroblast >3% of space. Muscle cells (up to 6 µm across and ~600 µm long, packed to almost 100,000 per mm²) have surface-to-volume ratio of 2.4 µm²/µm³ ~93% of cell volume is contractile apparatus, 3.1% mitochondria and 2.5% nucleus. Cell profiles are irregular but sectional area decreases regularly towards either end of the cell. Muscle cells are gathered into bundles (the mechanical units of detrusor), variable in length and size, but of constant width. The musculature is highly compact (without fascia or capsule) with smooth outer surfaces and extensive association and adhesion between its cells. Among many types of intercellular contact and junction, digitations are very common, each muscle cell issuing minute finger-like processes that abut on adjacent cells. Sealed apposition are wide areas of specialized contact, possibly forming a chamber between two muscle cells, distinct from the extracellular space at large (stromal space). The innervation is very dense, virtually all intramuscular axons being varicose (including afferent ones). There are identifiable neuro-muscular junctions on each muscle cell, often several junctions on a single cell. There are also unattached terminals. Fibroblasts (involved in the production of collagen), ~1% of the total number of cells, do not make specialized contacts.

Gastrointestinal smooth muscle research has evolved from studies on muscle strips to spatiotemporal mapping of whole organ motor and electrical activities. Decades of research on single muscle cells and small sections of isolated musculature from animal models has given us the groundwork for interpretation of human in vivo studies. Human gut motility studies have dramatically improved by high-resolution manometry and high-resolution electrophysiology. The details that emerge from spatiotemporal mapping of high-resolution data are now of such quality that hypotheses can be generated as to the physiology (in healthy subjects) and pathophysiology (in patients) of gastrointestinal (dys) motility. Such interpretation demands understanding of the musculature as a super-network of excitable cells (neurons, smooth muscle cells, other accessory cells) and oscillatory cells (the pacemaker interstitial cells of Cajal), for which mathematical modeling becomes essential. The developing deeper understanding of gastrointestinal motility will bring us soon to a level of precision in diagnosis of dysfunction that is far beyond what is currently available.

In the past few decades, solid evidence has been accumulated for the pivotal significance of immunoinflammatory processes in the initiation, progression, and exacerbation of many diseases and disorders. This groundbreaking view came from original works by Ross who first described that excessive inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall is essential for the pathogenesis of atherosclerosis (Ross, Nature 1993; 362(6423): 801–9). It is now widely recognized that both innate and adaptive immune reactions are avidly involved in the inflammation-related remodeling of many tissues and organs. When this state persists, irreversible fibrogenic changes would occur often culminating in fatal insufficiencies of many vital parenchymal organs such as liver, lung, heart, kidney and intestines. Thus, inflammatory diseases are becoming the common life-threatening risk for and urgent concern about the public health in developed countries (Wynn et al., Nature Medicine 2012; 18(7): 1028–40). Considering this timeliness, we organized a special symposium entitled “Implications of immune/inflammatory responses in smooth muscle dysfunction and disease” in the 58th annual meeting of the Japan Society of Smooth Muscle Research. This symposium report will provide detailed synopses of topics presented in this symposium; (1) the role of inflammasome in atherosclerosis and abdominal aortic aneurysms by Fumitake Usui-Kawanishi and Masafumi Takahashi; (2) Mechanisms underlying the pathogenesis of hyper-contractility of bronchial smooth muscle in allergic asthma by Hiroyasu Sakai, Wataru Suto, Yuki Kai and Yoshihiko Chiba; (3) Vascular remodeling in pulmonary arterial hypertension by Keizo Hiraishi, Lin Hai Kurahara and Ryuji Inoue.