ICUAP is independently associated with increased hospital mortality. Handgrip strength is also independently associated with poor hospital outcome and may serve as a simple test to identify ICUAP. Clinical trial registered with www.clinicaltrials.gov (NCT00106665).

Multiple and paradoxical effects of airway smooth muscle (ASM) 7-transmembrane-spanning receptors activated during asthma, or by treatment with bronchodilators such as β 2 -adrenergic receptor (β 2 AR) agonists, indicate extensive receptor crosstalk. We examined the signaling of the prostanoid-EP 1 receptor, since its endogenous agonist prostaglandin E 2 is abundant in the airway, but its functional implications are poorly defined. Activation of EP 1 failed to elicit ASM contraction in mouse trachea via this G αq -coupled receptor. However, EP 1 activation markedly reduced the bronchodilatory function of β 2 AR agonist, but not forskolin, indicating an early pathway interaction. Activation of EP 1 reduced β 2 AR-stimulated cAMP in ASM but did not promote or augment β 2 AR phosphorylation or alter β 2 AR trafficking. Bioluminescence resonant energy transfer showed EP 1 and β 2 AR formed heterodimers, which were further modified by EP 1 agonist. In cell membrane [ 35 S]GTPγS binding studies, the presence of the EP 1 component of the dimer uncoupled β 2 AR from G αs , an effect accentuated by EP 1 agonist activation. Thus alone, EP 1 does not appear to have a significant direct effect on airway tone but acts as a modulator of the β 2 AR, altering G αs coupling via steric interactions imposed by the EP 1 :β 2 AR heterodimeric signaling complex and ultimately affecting β 2 AR-mediated bronchial relaxation. This mechanism may contribute to β-agonist resistance found in asthma. IntroductionThe 7-transmembrane-spanning (7-TM-spanning) receptors represent the largest signaling family in the genome. We estimate that the lung expresses 25-50 7-TM receptors in airway epithelial cells, airway smooth muscle (ASM), pulmonary vasculature, alveolar walls, and resident immune cells (1). In regard to asthma, several 7-TM receptors play established roles in bronchoconstriction (e.g., M 3 -muscarinic receptor) and bronchodilation (e.g., β 2 -adrenergic receptor [β 2 AR]). Despite identification of the endogenous ligands and receptor localization, there are a number of 7-TM receptors expressed in the airway whose functions are unknown, or appear to function paradoxically, based on recombinantly expressed receptors in model cell systems. This lack of understanding of receptor function has impeded our ability to ascertain the role of these ligands (some of which are markedly increased in asthma) in the relaxation/contraction of ASM; thus the mechanistic basis of bronchial hyperreactivity and bronchoconstriction in asthma remains only partially understood. In many cases the basis for incomplete mechanistic information can be attributed to the nature of recombinant expression systems, which may not take

subtype 3 receptor (M3R); thromboxane A2 receptor (TXA2R); 5-hydroxytryptamine subtype 2 receptor (5-HT2R); phospholipase C (PLC); inositol 1,4,5 trisphosphate (IP3); enhanced pause (Penh); airway resistance (Raw); relative units (RUs); 125 I-cyanopindolol ( 125 I-CYP); β2AR overexpression (β2AR-OE).

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