Expression of airway hyperreactivity to acetylcholine as a simple autosomal recessive trait in mice

Abstract

An increased airway response to various bronchoconstricting agents is one of the hallmarks of asthma. An interdependence of heredity and environment appears to determine this nonspecific hyperreactivity of the airways. The present study describes the patterns of inheritance of the airway response to a direct mediator of smooth muscle contraction (acetylcholine) in A/J and C3H/HeJ inbred mice and their offspring. The mean airway response to acetylcholine was greater than sixfold higher in A/J mice as compared with C3H/HeJ mice. Two phenotypes were easily distinguished on the basis of airway responses to acetylcholine in the progeny of A/J and C3H/HeJ mice. These two phenotypes were termed HYPERREACTIVE (after the A/J strain) and HYPOREACTIVE (after the C3H/HeJ strain). The observed frequencies of HYPERREACTIVE and HYPOREACTIVE phenotypes in the (A/J x C3H/HeJ) F1; (C3H/HeJ x A/J) F1 x C3H/HeJ (C3H/HeJ backcross); and the [(A/J x C3H/HeJ) F1 x (C3H/HeJ x A/J) F1] F2 are consistent with a single autosomal recessive gene primarily controlling acetylcholine-mediated airway responses. This single gene difference in airway response is completely inhibited by atropine and therefore mediated entirely by the muscarinic acetylcholine receptor.

CpG Oligodeoxynucleotides Can Reverse Th2-Associated Allergic Airway Responses and Alter the B7.1/B7.2 Expression in a Murine Model of Asthma

“…acetylcholine challenge, as previously described (9,21). The time-integrated changes in peak airway pressure, referred to as the airway pressure-time index (centimeters H 2 O-s) were calculated and served as measurements of airway responsiveness.…”

The contribution of Ca2+ signaling and Ca2+ sensitivity to the regulation of airway smooth muscle contraction is different in rats and mice

“…For example, mouse airway SMCs seem to have a low Ca 2ϩ sensitivity coupled with fast agonistinduced Ca 2ϩ oscillations, whereas mouse pulmonary arteriole SMCs appear to have higher Ca 2ϩ sensitivity coupled with slow agonist-induced Ca 2ϩ oscillations (1,25,26). Similarly, agonist-induced airway contraction varies between species or different strains of the same species with certain strains of mice and rats displaying spontaneous, innate airway hyperresponsiveness (3,9,17,19,24,35). Understanding how alterations in the regulatory mechanisms that are responsible for this physiological variation between species or strains is extremely valuable because it is possible that similar alterations may also account for enhanced airway contraction in asthma.…”

Male sex hormones promote vagally mediated reflex airway responsiveness to cholinergic stimulation

“…Furthermore, and perhaps most importantly, doing so more closely relates these models to the human conditions they are intended to emulate. As such, it is somewhat surprising that whereas factors including genetic background and obesity are recognized to influence lung function, respiratory mechanics and airway responsiveness in mice (12,15,22,26,27), the potential influence of sex in murine studies of lung function and in murine models of lung disease is often overlooked.…”