In vitro-induced human airway hyperresponsiveness to bradykinin

Abstract

aaAirway inflammation is one of the main features of asthma. It has been well established that people with respiratory infections may experience increased bronchial reactivity and impaired bronchial airflow [1,2]. Inhalation of endotoxin or lipopolysaccharide (LPS), a component of the outer cell wall of Gram-negative bacteria, has been reported to induce airway hyperresponsiveness in both normal [3] and asthmatic subjects [4]. The pathophysiological mechanisms underlying these changes after administration of LPS to the airways are not fully understood. Effects of LPS are likely to be indirect, through the activation of various inflammatory cells [5] which release the different endogenous inflammatory mediators and cytokines responsible for the host response. Among them, interleukin (IL)-1β is notable [6-8] and has been described as inducing airway hyperresponsiveness. Indeed, intratracheal administration of IL-1β has been shown to induce airway hyperresponsiveness to bradykinin in rats [9].Bradykinin has been implicated in the pathophysiology of asthma [10]. Inhaled bradykinin is a potent bronchoconstrictor in asthmatic patients, but is almost ineffective in normal subjects [11]. This feature may explain a key mechanism in the occurrence of airway hyperresponsiveness, which is a pathological characteristic of asthma.It has been established that bradykinin-induced human isolated bronchi contraction is linked to bradykinin B 2 receptor stimulation and subsequent prostanoid release [12][13][14]. The purpose of this study was to determine whether LPS and thereafter IL-1β induce hyperresponsiveness to bradykinin on human bronchial tissue in vitro and, if so, to analyse the mechanism of this hyperresponsiveness. Materials and methods Human bronchial tissue preparationBronchial tissues were removed from 22 patients (mean age 63 yrs, range 49-79 yrs) with lung cancer at the time of the surgical procedure. All were previous smokers. None were asthmatic. Just after resection, segments of bronchi with an inner diameter of 0.5-1 mm were taken from as far away as possible from the malignancy. They were placed in oxygenated Krebs-Henseleit solution (NaCl 119 mM, KCl 5.4 mM, CaCl 2 2.5 mM, KH 2 PO 4 0.6 mM, MgSO 4 1.2 mM, NaHCO 3 25 mM, glucose 11.7 mM) and stored overnight at 4°C. After removal of adhering fat and connective tissues, four to eight rings of the same bronchus were prepared. Each set of bronchial rings was suspended under an initial tension of 1.5 g in a 5 mL organ bath containing Krebs-Henseleit solution, bubbled with 95% O 2 /5% CO 2 and maintained at 37°C. The tissue was allowed to equilibrate over 1 h, during which time the KrebsHenseleit solution was changed every 15 min. Changes in LPS (100 ng·mL -1 for 3-6 h) and IL-1β (3×10 -10 and 3×10 -9 M for 20 min to 3 h) time-dependently potentiated bradykinin-induced contraction. This contraction was abolished, as in control experiments, by indomethacin (10 -6 M) or by the thromboxane (Tx) receptor antagonist GR 32191 but not by the cyclo-oxygenase-2 inhibitor, CG...

Dual Role of Interleukin-1α in Delayed-Type Hypersensitivity and Airway Hyperresponsiveness

“…In addition, delivery of an adenovirus expressing IL-1RA after sensitization and before airway antigen challenge alleviated AHR, pulmonary infiltration with eosinophils and neutrophils and decreased IL-5 levels [38], IL-1RA abrogated both the IL-5- and IgE-induced changes in airway smooth muscle responsiveness in asthma [39], whereas, in contrast, IL-1β and TNF-α increased airway smooth muscle response to various contractile agonists, e.g. methacholine [40]. Finally, IL-1β and TNF-α induce NF-ĸB-dependent CCL28 induction, a mucosal chemokine that attracts eosinophils and T cells via CCR3 and CCR10 [41].…”

Nerve growth factor is released by IL-1 and induces hyperresponsiveness of the human isolated bronchus

“…Previous studies reported that interleukin (IL)-1b induces AHR in several animal models [11][12][13]. In addition, BARCHASZ et al [14] described that IL1b causes AHR to the NK-1 tachykinin receptor agonist [Sar 9 ,Met(O 2 ) 11 ]-substance P (SP) in the human isolated bronchus.…”

Airway Smooth Muscle in Asthma Symptoms: Culprit but Maybe Innocent

“…At the molecular level, several asthma triggers have been shown to increase ASM contractility ex vivo. For example, ASM contractility has been shown to be enhanced following prolong (at least 16 h) incubation with atopic serum (15,19,78,89,91,161,211,245,246), IgE immune complex (80,89,250) and exogenous asthma triggers such as the house dust mite allergen Der p 1 (82), the bacterial endotoxin lipopolysaccharide (LPS) (8,166,216,220) and the rhinovirus (serotype 16) (78,81) or the virus mimetic toll-like receptor (TLR)3 ligand polyinosinic polycytidylic acid (poly-IC) (8). Most of these studies assessed ASM contractility by measuring its force-generating capacity.…”

“…The half-time of relaxation after short EFS-induced tetani has also been shown to increase (double) in ASM strips derived from dogs sensitized to ragweed (109). The effect of asthma triggers on ex vivo ASM contractility can be indirect; i.e., due to an autocrine loop of mediators that are produced by the ASM in response to asthma triggers (79,80,91,166). In vivo, the paracrine influence of other cells that are responsive to asthma triggers can also impact ASM contractility.…”

“…In turn, the effect of these mediators is not always direct. For example, the potentiating effect of IL-1 on bradykinin-induced contraction is due to a greater release of thromboxane (Tx)A 2 in response to bradykinin (166). As for the asthma triggers, most of these studies assessed ASM contractility by measuring its force-generating capacity.…”