Essential role of smooth muscle Rac1 in severe asthma-associated airway remodelling.

BACKGROUND: Severe asthma is a chronic lung disease characterised by inflammation, airway hyperresponsiveness (AHR) and airway remodelling. The molecular mechanisms underlying uncontrolled airway smooth muscle cell (aSMC) proliferation involved in pulmonary remodelling are still largely unknown. Small G proteins of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of smooth muscle functions and we recently demonstrated that Rac1 is activated in aSMC from allergic mice. The objective of this study was to assess the role of Rac1 in severe asthma-associated airway remodelling. METHODS AND RESULTS: Immunofluorescence analysis in human bronchial biopsies revealed an increased Rac1 activity in aSMC from patients with severe asthma compared with control subjects. Inhibition of Rac1 by EHT1864 showed that Rac1 signalling controlled human aSMC proliferation induced by mitogenic stimuli through the signal transducer and activator of transcription 3 (STAT3) signalling pathway. In vivo, specific deletion of Rac1 in SMC or pharmacological inhibition of Rac1 by nebulisation of NSC23766 prevented AHR and aSMC hyperplasia in a mouse model of severe asthma. Moreover, the Rac1 inhibitor prevented goblet cell hyperplasia and epithelial cell hypertrophy whereas treatment with corticosteroids had less effect. Nebulisation of NSC23766 also decreased eosinophil accumulation in the bronchoalveolar lavage of asthmatic mice. CONCLUSION: This study demonstrates that Rac1 is overactive in the airways of patients with severe asthma and is essential for aSMC proliferation. It also provides evidence that Rac1 is causally involved in AHR and airway remodelling. Rac1 may represent as an interesting target for treating both AHR and airway remodelling of patients with severe asthma.

Smooth muscle Rac1 contributes to pulmonary hypertension.

BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) is a multifactorial chronic disease characterized by an increase in pulmonary artery (PA) resistance leading to right ventricle (RV) failure. Endothelial dysfunction and alteration of NO/cGMP signalling in PA plays a major role in PH. We recently described the involvement of the Rho protein Rac1 in the control of systemic blood pressure through its involvement in NO-mediated relaxation of arterial smooth muscle cell (SMC). The aim of this study was to analyse the role of SMC Rac1 in PH. EXPERIMENTAL APPROACH: PH is induced by exposure of control and SMC Rac1-deficient (SM-Rac1-KO) mice to chronic hypoxia (10% O2 , 4 weeks). PH is assessed by the measurement of RV systolic pressure and hypertrophy. PA reactivity is analysed by isometric tension measurements. PA remodelling is quantified by immunofluorescence in lung sections and ROS are detected using the dihydroethidium probe and electronic paramagnetic resonance analysis. Rac1 activity is determined by immunofluorescence. KEY RESULTS: Rac1 activation in PA of hypoxic mice and patients with idiopathic PH. Hypoxia-induced rise in RV systolic pressure, RV hypertrophy and loss of endothelium-dependent relaxation were significantly decreased in SM-Rac1-KO mice compared to control mice. SMC Rac1 deletion also limited hypoxia-induced PA remodelling and ROS production in pulmonary artery smooth muscle cells (PASMCs). CONCLUSION AND IMPLICATIONS: Our results provide evidence for a protective effect of SM Rac1 deletion against hypoxic PH. Rac1 activity in PASMCs plays a causal role in PH by favouring ROS-dependent PA remodelling and endothelial dysfunction induced by chronic hypoxia.

Bronchial smooth muscle cell in asthma: where does it fit?

Asthma is a frequent respiratory condition whose pathophysiology relies on altered interactions between bronchial epithelium, smooth muscle cells (SMC) and immune responses. Those leads to classical hallmarks of asthma: airway hyper-responsiveness, bronchial remodelling and chronic inflammation. Airway smooth muscle biology and pathophysiological implication in asthma are now better understood. Precise deciphering of intracellular signalling pathways regulating smooth muscle contraction highlighted the critical roles played by small GTPases of Rho superfamily. Beyond contractile considerations, active involvement of airway smooth muscle in bronchial remodelling mechanisms is now established. Not only cytokines and growth factors, such as fibroblats growth factor or transforming growth factor-ß, but also extracellular matrix composition have been demonstrated as potent phenotype modifiers for airway SMC. Although basic science knowledge has grown significantly, little of it has translated into improvement in asthma clinical practice. Evaluation of airway smooth muscle function is still limited to its contractile activity. Moreover, it relies on tools, such as spirometry, that give only an overall assessment and not a specific one. Interesting technics such as forced oscillometry or specific imagery (CT and MRI) give new perspectives to evaluate other aspects of airway muscle such as bronchial remodelling. Finally, except for the refinement of conventional bronchodilators, no new drug therapy directly targeting airway smooth muscle proved its efficacy. Bronchial thermoplasty is an innovative and efficient therapeutic strategy but is only restricted to a small proportion of severe asthmatic patients. New diagnostic and therapeutic strategies specifically oriented toward airway smooth muscle are needed to improve global asthma care.

Efficacy of an orally administered anti-diarrheal probiotic paste (Pro-Kolin Advanced) in dogs with acute diarrhea: A randomized, placebo-controlled, double-blinded clinical study.

BACKGROUND: Acute diarrhea is a common clinical presentation of dogs. The effect of specific anti-diarrheal probiotic pastes (ADPPs) in the management of acute, uncomplicated diarrhea in dogs is unknown. HYPOTHESIS: Administration of an ADPP containing Enterococcus faecium 4b1707 will improve the clinical outcome of acute, uncomplicated diarrhea in dogs compared to placebo. ANIMALS: One hundred forty-eight client-owned dogs with acute diarrhea as the main clinical sign. METHODS: Double-blinded, placebo-controlled, randomized, blocked, multicenter clinical field study conducted at 14 primary care veterinary practices in the United Kingdom and Ireland. RESULTS: The ADPP was associated with better clinical outcome compared to placebo in dogs with acute, uncomplicated diarrhea. Dogs in the ADPP group had a significantly shorter duration of diarrhea (ADPP: median, 32 hours; 95% confidence interval [CI], 2-118; n = 51; Placebo: median, 47 hours; 95% CI, 4-167; n = 58; P = .008) and the rate of resolution of diarrhea was 1.60 times faster in the ADPP group than in the Placebo group (ratio, 1.60; 95% CI, 1.08-2.44; P = .02). Fewer dogs required additional medical intervention (AMI) for non-improvement or worsening in the ADPP group compared to the Placebo group (3.5% of dogs and 14.8% of dogs, respectively), with a relative risk of 0.88 (P = .04; AMI, ADPP, 3.5%, 2/57 dogs; Placebo, 14.8%, 9/61 dogs; relative risk, 0.88; 95% CI, 0.77-0.99). CONCLUSION AND CLINICAL IMPORTANCE: The ADPP may accelerate resolution of acute diarrhea in dogs and decrease the requirement for AMI.

Caring in pediatric emergency nursing.

An environment committed to providing family-centered care to children must be aware of the nurse caring behaviors important to parents of children. This descriptive study assessed the psychometrics of a revised version of the Caring Behaviors Assessment (CBA) and examined nurse caring behaviors identified as important to the parents of pediatric patients in a pediatric emergency department. Jean Watson's theory of human caring provided the study's theoretical underpinnings. The instrument psychometrics was determined through an index of content validity (CVI) and internal consistency reliability. The instrument was determined to be valid (CVI = 3.75) and reliable (Cronbach's alpha = .971). The revised instrument was completed by a stratified, systematic random sample of 300 parents of pediatric emergency patients. Participants rated the importance of each item for making the child feel cared for by nurses. Individual survey item means were computed. Items with the highest means represented the most important nurse caring behaviors. Leading nurse caring behaviors centered on carative factors of "human needs assistance" and "sensitivity to self and others." Nearly all nurse caring behaviors were important to the parents of pediatric patients, although some behaviors were not priority. It is important for nurses to provide family-centered care in a way that demonstrates nurse caring.