Rationale: Acute lung injury (ALI) is a debilitating condition associated with severe skeletal muscle weakness that persists in humans long after lung injury has resolved. The molecular mechanisms underlying this condition are unknown. Objectives: To identify the muscle-specific molecular mechanisms responsible for muscle wasting in a mouse model of ALI. Methods: Changes in skeletal muscle weight, fiber size, in vivo contractile performance, and expression of mRNAs and proteins encoding muscle atrophy-associated genes for muscle ring finger-1 (MuRF1) and atrogin1 were measured. Genetic inactivation of MuRF1 or electroporationmediated transduction of miRNA-based short hairpin RNAs targeting either MuRF1 or atrogin1 were used to identify their role in ALIassociated skeletal muscle wasting. Measurements and Main Results: Mice with ALI developed profound muscle atrophy and preferential loss of muscle contractile proteins associated with reduced muscle function in vivo. Although mRNA expression of the muscle-specific ubiquitin ligases, MuRF1 and atrogin1, was increased in ALI mice, only MuRF1 protein levels were up-regulated. Consistent with these changes, suppression of MuRF1 by genetic or biochemical approaches prevented muscle fiber atrophy, whereas suppression of atrogin1 expression was without effect. Despite resolution of lung injury and down-regulation of MuRF1 and atrogin1, force generation in ALI mice remained suppressed. Conclusions: These data show that MuRF1 is responsible for mediating muscle atrophy that occurs during the period of active lung injury in ALI mice and that, as in humans, skeletal muscle dysfunction persists despite resolution of lung injury.Keywords: skeletal muscle atrophy; intensive care unit-acquired weakness; critical illness myopathy; muscle atrophy genes; proteasomal-mediated protein degradation Acute lung injury (ALI) is a syndrome characterized by the acute onset of pulmonary infiltrates and respiratory failure often leading to the need for mechanical ventilation (1). Approximately 200,000 people per year develop ALI in the United States, with mortality high at 30-40% (2). A common complication associated with ALI is skeletal muscle weakness. Weakness in these patients results in decreased long-term mobility and functional status. Skeletal muscle weakness is initiated early in the course of ALI, and has been shown to persist in a large percentage of patients for up to 5 years after resolution of lung injury and hospital discharge (3-6). Although multiple factors may contribute to ALI-induced muscle atrophy including reduced nutrition, inactivity caused by bed rest, and systemic inflammation, the etiology of ALI-associated skeletal muscle atrophy remains incompletely understood.Skeletal muscle weakness is a common finding not only among patients with ALI, but also in patients with other critical illnesses. Clinically apparent weakness is present in 20-50% of patients with critical illness and has been shown to be an independent risk factor for mortality in these patients (3,5,7,8)....

Sphingosine 1-phospate (S1P) has been demonstrated to protect against the formation of lipopolysaccharide (LPS)-induced lung edema when administered concomitantly with LPS. In the present study, we sought to determine the effectiveness of S1P to attenuate lung injury in a translationally relevant canine model of acute lung injury (ALI) when administered as rescue therapy. Secondarily, we examined whether the attenuation of LPS-induced physiological lung injury following administration of S1P was, at least in part, due to an alteration in local and/or systemic inflammatory cytokine expression. We prospectively examined 18 one-year old male beagles in which we instilled bacterial LPS (2-4 mg/kg) intratracheally followed in one hour with intravenous S1P (85 μg/kg) or vehicle and eight hours of high tidal volume mechanical ventilation. S1P attenuated the formation of shunt fraction (32%) and both the presence of protein (72%) and neutrophils (95%) in bronchoalveolar lavage (BAL) fluid compared to vehicle controls. Although lung tissue inflammatory cytokine production was found to vary regionally throughout the LPS-injured lung, S1P did not alter the expression pattern. Similarly, BAL cytokine production was not significantly altered by intravenous S1P in this model. Interestingly, S1P potentiated the LPS-induced systemic production of three inflammatory cytokines, TNF-α (6-fold), KC (1.2-fold), and IL-6 (3-fold), without resulting in end-organ dysfunction. In conclusion, intravenous S1P reduces inflammatory lung injury when administered as rescue therapy in our canine model of LPS-induced ALI. This improvement is observed in the absence of changes in local pulmonary inflammatory cytokine production and an augmentation of systemic inflammation.Corresponding Address:

Background Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. ARC (Apoptosis Repressor with Caspase Recruitment Domain) is an inhibitor of multiple forms of cell death known to be abundantly expressed in striated muscle. We show for the first time that ARC is expressed in arterial smooth muscle cells of the pulmonary vasculature and is markedly up-regulated in several experimental models of PH. In this study, we test the hypothesis that ARC expression is essential for the development of chronic hypoxia-induced PH. Methods and Results Experiments in which cells or mice were rendered ARC-deficient revealed that ARC not only protected pulmonary arterial smooth muscle cells from hypoxia-induced death, but also facilitated growth factor-induced proliferation and hypertrophy and hypoxia-induced down-regulation of selective voltage-gated potassium channels, the latter a hallmark of the syndrome in humans. Moreover, ARC-deficient mice exhibited diminished vascular remodeling, increased apoptosis, and decreased proliferation in response to chronic hypoxia, resulting in marked protection from PH in vivo. Patients with PH have significantly increased ARC expression not only in remodeled vessels but also in the lumen-occluding lesions associated with severe disease. Conclusions These data show that ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome.

Hoag JB, Liu M, Easley RB, Britos-Bray MF, Kesari P, Hassoun H, Haas M, Tuder RM, Rabb H, Simon BA. Effects of acid aspiration-induced acute lung injury on kidney function. Am J Physiol Renal Physiol 294: F900-F908, 2008. First published February 6, 2008 doi:10.1152/ajprenal.00357.2007.-Acute lung injury (ALI) in combination with acute kidney injury carries a mortality approaching 80% in the intensive care unit. Recently, attention has focused on the interaction of the lung and kidney in the setting of ALI and mechanical ventilation (MV). Small animal models of ALI and MV have demonstrated changes in inflammatory mediators, water channels, apoptosis, and function in the kidney early in the course of injury. The purpose of this investigation was to test the hypothesis that ALI and injurious MV cause early, measurable changes in kidney structure and function in a canine HCl aspiration model of ALI when hemodynamics and arterial blood gas tensions are carefully controlled. Intratracheal HCl induced profound ALI as demonstrated by increased shunt fraction and airway pressures compared with sham injury. Shaminjured animals had similar mean arterial pressure and arterial PCO 2 and HCO3 levels compared with injured animals. Measurements of renal function including renal blood flow, urine flow, serum creatinine, glomerular filtration rate, urine albumin-to-creatinine ratio, and kidney histology scores were not different between groups. With maintenance of hemodynamic parameters and alveolar ventilation, ALI and injurious MV do not alter kidney structure and function early in the course of injury in this acid aspiration canine model. Kidney injury in large animal models may be more similar to humans and may differ from results seen in small animal models. mechanical ventilation; biotrauma; renal function PATIENTS WITH COMBINED ACUTE lung injury (ALI) and acute kidney injury (AKI) have a mortality rate approaching 80% in the intensive care unit (17). Considerable clinical and experimental data support the existence of a direct pulmonary-renal interaction in the setting of ALI and the acute respiratory distress syndrome (ARDS). In the Acute Respiratory Distress Syndrome Network study (1) comparing low tidal volume to "conventional" tidal volume (V T ) ventilation, protective modes of ventilation not only improved mortality from ARDS, but led to improved function in other organ systems. Specifically, patients receiving 6 ml/kg V T had a lower number of days with renal failure in the first 28 days compared with patients receiving 12 ml/kg V T (1). Similarly, a smaller study (24) showed a decrease in the number of patients developing renal failure in the first 72 to 96 h when low tidal volume ventilation was used.Likewise, animal models of ALI and mechanical ventilation have been used in an effort to determine mechanisms of organ cross talk in response to injury. Most well-described are the influences of mechanical ventilation in the setting of ALI on hemodynamics, thus modifying renal blood flow. Positive end-expiratory pre...

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