Increased mechanical strain imposed on murine lungs during ventilation in vivo depresses airway responsiveness and activation of protein kinase Akt

Abstract

Continuous positive airway pressure (CPAP) administered to tracheostomized rabbits and ferrets for 4 days or 2 wk suppresses bronchial reactivity in vivo and suppresses airway reactivity in lobes and tracheal segments isolated from these animals. In vitro studies of canine tracheal smooth muscle tissues indicate that mechanical loading suppresses the activation of the growth regulatory kinase, Akt, and that Akt is a negative regulator of smooth muscle differentiation. The transduction of mechanical signals in the tracheal tissues in vitro is mediated by integrin-associated adhesion complexes. To determine whether airway responsiveness and Akt activation are modulated by mechanical loads applied for short time periods to the airways of living animals in vivo, mice were mechanically ventilated for 2 h with high (5 cmH2O) or low (0-1 cmH2O) positive end-expiratory pressure (PEEP) and then ventilated at low PEEP for 30 min. Ventilation of mice with PEEP in vivo for 2 h depressed airway responsiveness to methacholine measured in vivo subsequent to the PEEP treatment. Airway narrowing in vitro in intraparenchymal airways in isolated lung slices and contractile responses of isolated tracheal segments in vitro were suppressed for at least 6 h subsequent to the in vivo exposure to PEEP. Tracheal segments isolated from high PEEP-treated mice exhibited significantly lower levels of Akt activation than tracheae from low PEEP-treated mice. The results indicate that mechanical loads imposed in vivo result in physiological and biochemical changes in the airway tissues after a relatively short 2-h period of in vivo loading.

Increased airway reactivity in a neonatal mouse model of continuous positive airway pressure

“…Few neonatal animal studies have investigated the effects of CPAP on neonatal AW reactivity and its effects on adults are conflicting ( 17 – 21 , 28 ). The discrepancies between these studies suggest the effects of CPAP are multifactorial and could depend on numerous factors including the duration, intensity and experimental setting in which positive pressure was delivered to the lung.…”

Hydraulic Pressure During Fluid Flow Regulates Purinergic Signaling and Cytoskeleton Organization of Osteoblasts

“…Previous reports in lung tissue and smooth muscle cells have found that an increase in pressure on the order of 1 mmHg decreases focal adhesion activation of the protein kinase, Akt. 42, 43 Focal adhesions that anchor the osteoblasts to the extracellular matrix play a key role in translating these mechanical forces to the intracellular cytoskeleton framework and into a biochemical response. The interaction between focal adhesions and the extracellular matrix can change under different mechanical loads due to conformational changes to the integrin structure.…”

Does smooth muscle in an intact airway undergo length adaptation during a sustained change in transmural pressure?

“…Furthermore, the effects of CPAP persisted for at least 24 h (61). In a recent study by Xue and colleagues (63), CPAP for only 2 h was sufficient to alter airway responsiveness in mice.…”

“…Several previous studies examining the effect of chronic exposure to increased P tm on airway function all show that chronic inflation suppresses airway narrowing (52,(61)(62)(63). Indeed, continuous positive airway pressure (CPAP) has been suggested as a novel treatment for asthma (43).…”