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ABSTRACT: Intensive-Care Unit Acquired Weakness (ICUAW) begins within hours of mechanical ventilation and may not be completely reversible over time. It represents a major functional morbidity of critical illness and is an important patient-centred outcome with clear implications for quality of life and resumption of prior work and lifestyle. There is heterogeneity in functional outcome related to ICUAW across different patient populations after an episode of critical illness. This state-of-the art review argues that this observed heterogeneity may represent a clinical spectrum of disability in which there are recognizable clinical phenotypes for outcome according to age, burden of co-morbid illness and ICU length of stay. Further, that these functional outcomes are modified by mood, cognition and caregiver physical and mental health. This proposed construct of clinical phenotype will be used as a framework for a review of the current literature on the molecular biology of muscle and nerve injury. This translational approach for the development of models pairing clinical phenotypes for different functional outcome after critical illness with molecular mechanism of injury may offer unique insights into diagnosis and treatment of muscle and nerve lesions.
American Journal of Respiratory and Critical Care Medicine 11/2012; · 11.08 Impact Factor
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ABSTRACT: ICU-acquired weakness (ICUAW) is now recognized as a major complication of critical illness. There is no doubt that ICUAW is prevalent - some might argue ubiquitous - after critical illness, but its true role, the interaction with preexisting nerve and muscle lesions as well as its contribution to long-term functional disability, remains to be elucidated.
In this article, we review the current state-of-the-art of the basic pathophysiology of nerve and muscle weakness after critical illness and explore the current literature on ICUAW with a special emphasis on the most important mechanisms of weakness.
Variable contributions of structural and functional changes likely contribute to both early and late myopathy and neuropathy, although the specifics of the temporality of both processes, and the influence patient comorbidities, age, and nature of the ICU insult have on them, remain to be determined.
Current opinion in critical care 08/2012; 18(5):509-17. · 2.67 Impact Factor
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ABSTRACT: The increase of airway smooth muscle (ASM) mass in asthma results from hypertrophic and hyperplastic stimuli, and leads to an increase in cellular contractile proteins. However, little evidence correlates the relative contributions of hypertrophic and hyperplastic muscle with functional effects on airway resistance. We performed a ventilator-based assessment of respiratory mechanics and responsiveness to methacholine in a murine model of acute (3-week) ovalbumin (OVA)-induced airway inflammation, compared with a chronic (12-week) model. We correlated functional changes in airways Newtonian resistance (RN), peripheral tissue damping (G), and elastance (H) with the relative contributions of proliferation, hypertrophy, and apoptosis to increased ASM mass. Immunohistochemical analyses of treated (OVA-sensitized and OVA-challenged; OVA/OVA) and control (OVA-sensitized and saline-challenged; OVA/PBS) murine lungs showed an increase in ASM area in chronic, but not acute, OVA/OVA-treated mice that correlated positively with increased airway resistance to methacholine. Acute OVA/OVA-treated ASM exhibited an increase in proliferation with diminished apoptosis, which resolved in the chronic OVA/OVA model. Chronic OVA/OVA-treated ASM exhibited hypertrophy. Distinct temporal differences exist in the response of murine airways to antigenic challenge. We report that ASM proliferation and diminished apoptosis occur during the acute phase, followed by the development of smooth muscle hypertrophy and an increased muscle mass with chronic challenge, that correlate strongly with increased airway Newtonian resistance. The identification of a functionally relevant hypertrophic bronchial muscle mass highlights the possibility of regulating airway muscle hypertrophy as a novel therapeutic target in asthma.
American Journal of Respiratory Cell and Molecular Biology 11/2011; 46(4):532-40. · 5.13 Impact Factor
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Ali Akram,
Bing Han,
Hussain Masoom,
Claudia Peng,
Emily Lam,
Michael L Litvack,
Xiaohui Bai,
Yuexin Shan,
Tsonwin Hai, Jane Batt,
Arthur S Slutsky,
Haibo Zhang,
Wolfgang M Kuebler,
Jack J Haitsma,
Mingyao Liu,
Claudia C dos Santos
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ABSTRACT: Ventilator-induced lung injury (VILI) significantly contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury. Understanding the molecular basis for response to cyclic stretch (CS) and its derangement during high-volume ventilation is of high priority.
To identify specific molecular regulators involved in the development of VILI.
We undertook a comparative examination of cis-regulatory sequences involved in the coordinated expression of CS-responsive genes using microarray analysis. Analysis of stretched versus nonstretched cells identified significant enrichment for genes containing putative binding sites for the transcription factor activating transcription factor 3 (ATF3). To determine the role of ATF3 in vivo, we compared the response of ATF3 gene-deficient mice to wild-type mice in an in vivo model of VILI.
ATF3 protein expression and nuclear translocation is increased in the lung after mechanical ventilation in wild-type mice. ATF3-deficient mice have greater sensitivity to mechanical ventilation alone or in conjunction with inhaled endotoxin, as demonstrated by increased cell infiltration and proinflammatory cytokines in the lung and bronchoalveolar lavage, and increased pulmonary edema and indices of tissue injury. The expression of stretch-responsive genes containing putative ATF3 cis-regulatory regions was significantly altered in ATF3-deficient mice.
ATF3 deficiency confers increased sensitivity to mechanical ventilation alone or in combination with inhaled endotoxin. We propose ATF3 acts to counterbalance CS and high volume-induced inflammation, dampening its ability to cause injury and consequently protecting animals from injurious CS.
American Journal of Respiratory and Critical Care Medicine 04/2010; 182(4):489-500. · 11.08 Impact Factor
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ABSTRACT: Skeletal muscle atrophy in individuals with advanced chronic obstructive pulmonary disease (COPD) is associated with diminished quality of life, increased health resource use, and worsened survival. Muscle wasting results from an imbalance between protein degradation and synthesis, and is enhanced by decreased regenerative repair. We investigated the activation of cellular signaling networks known to mediate muscle atrophy and regulate muscle regenerative capacity in rodent models, in individuals with COPD (FEV(1) < 50% predicted). Nine patients with COPD and nine control individuals were studied. Quadriceps femoris muscle isometric contractile force and cross-sectional area were confirmed to be significantly smaller in the patients with COPD compared with control subjects. The vastus lateralis muscle was biopsied and muscle transcript and/or protein levels of key components of ubiquitin-mediated proteolytic systems (MuRF1, atrogin-1, Nedd4), inflammatory mediators (IkappaBalpha, NF-kappaBp65/p50), AKT network (AKT, GSK3beta, p70S6 kinase), mediators of autophagy (beclin-1, LC3), and myogenesis (myogenin, MyoD, Myf5, myostatin) were determined. Atrogin-1 and Nedd4, two ligases regulating ubiquitin-mediated protein degradation and myostatin, a negative regulator of muscle growth, were significantly increased in the muscle of patients with COPD. MuRF1, Myf5, myogenin, and MyoD were not differentially expressed. There were no differences in the level of phosphorylation of AKT, GSK3beta, p70S6kinase, or IkappaBalpha, activation of NF-kappaBp65 or NF-kappaBp50, or level of expression of beclin-1 or LC3, suggesting that AKT signaling was not down-regulated and the NF-kappaB inflammatory pathway and autophagy were not activated in the COPD muscle. We conclude that muscle atrophy associated with COPD results from the recruitment of specific regulators of ubiquitin-mediated proteolytic pathways and inhibition of muscle growth.
American Journal of Respiratory Cell and Molecular Biology 06/2009; 42(4):461-71. · 5.13 Impact Factor
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ABSTRACT: The ubiquitin-proteasome system is a key proteolytic pathway activated during skeletal muscle atrophy. The proteasome, however, cannot degrade intact myofibrils or actinomyosin complexes. In rodent models of diabetes mellitus and uremia, caspase-3 is involved in actinomyosin cleavage, generating fragments that subsequently undergo ubiquitin-proteasome-mediated degradation. Here, we demonstrate that caspase-3 also mediates denervation-induced muscle atrophy. At 2 wk after tibial nerve transection, the denervated gastrocnemius of caspase-3-knockout mice weighed more and demonstrated larger fiber-type-specific cross-sectional area than the denervated gastrocnemius of wild-type mice. However, there was no difference between caspase-3-knockout and wild-type denervated muscles in the magnitude or pattern of actinomyosin degradation, as determined by Western blotting for actin and the 14-kDa actin fragment. Similarly, there was no difference between caspase-3-knockout and wild-type denervated muscles in the magnitude of increase in proteasome activity, total protein ubiquitination, or atrogin-1 and muscle-specific ring finger protein 1 transcript levels. In contrast, there was an increase in TdT-mediated dUTP nick end label-positive nuclei in the denervated muscle of wild-type compared with caspase-3-knockout mice. Apoptotic signaling upstream of caspase-3 remained intact, with equivalent mitochondrial Bax translocation and cytochrome c release and caspase-9 activation in the denervated gastrocnemius muscle of wild-type and caspase-3-knockout mice. In contrast, diminished poly(ADP-ribose) polymerase cleavage in the denervated muscle of caspase-3-knockout compared with wild-type mice revealed that apoptotic signaling downstream of caspase-3 was impaired, suggesting that the absence of caspase-3 protects against denervation-induced muscle atrophy by suppressing apoptosis as opposed to ubiquitin-proteasome-mediated protein degradation.
Journal of Applied Physiology 05/2009; 107(1):224-34. · 3.75 Impact Factor
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ABSTRACT: The inositol phosphatase, MTMR4 (myotubularin-related protein 4), was identified as a novel interactor of the ubiquitin ligase Nedd4 (neural-precursor-cell-expressed developmentally down-regulated 4). hMTMR4 (human MTMR4) and Nedd4 co-immunoprecipitated and co-localized to late endosomes. The PY (Pro-Tyr) motif of hMTMR4 binds to WW (Trp-Trp) domains of hNedd4. MTMR4 expression was decreased in atrophying muscle, whereas Nedd4 expression was increased and hMTMR4 was ubiquitinated by hNedd4, suggesting that this novel interaction may underlie the biological process of muscle breakdown.
Biochemical Journal 02/2009; 419(1):57-63. · 4.90 Impact Factor
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ABSTRACT: Despite the recent and marked improvement in short-term mortality after critical illness, significant morbidities persist for many patients following hospital discharge. This article discusses the risk factors for muscle, nerve, and brain dysfunction after critical illness and preliminary basic science data to support possible pathophysiologic mechanisms mediating this disability. Additionally, it presents a roadmap outlining future directions in this area of research.
Critical Care Clinics 02/2008; 24(1):179-99, x. · 2.05 Impact Factor
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ABSTRACT: Skeletal muscle function and viability are dependent upon intact innervation. Peripheral nerve injury and muscle denervation cause muscle atrophy. Time to re-innervation is one of the most important determinants of functional outcome. While short-term denervation can result in nearly fully reversible changes in muscle mass, prolonged denervation leads to irreversible muscle impairment from profound atrophy, myocyte death and fibrosis. We performed transcriptional profiling to identify genes that were altered in expression in short-term (1 month) and long-term (3 month) denervated muscle and validated the microarray data by RT-PCR and Western blotting. Genes controlling cell death, metabolism, proteolysis, stress responses and protein synthesis/translation were altered in expression in the denervated muscle. A differential pattern of expression of genes encoding cell cycle regulators and extracellular matrix components was identified that correlated with the development of irreversible post-denervation changes. Genes encoding mediators of protein degradation were differentially expressed between 1 and 3 month denervated muscle suggesting different signaling networks are recruited over time to induce and maintain muscle atrophy. Understanding of the timing and type of pathological processes that are triggered by denervation may allow the design of interventions that delay or protect muscle from loss of nerve function.
The FASEB Journal 02/2006; 20(1):115-7. · 5.71 Impact Factor
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ABSTRACT: Adult respiratory diseases in the developing world are a major burden in terms of morbidity and mortality and, particularly as related to chronic respiratory disease, are of increasing concern (Murray and Lopez 1996). For many years, the leading cause of adult respiratory disease mortality has been tuberculosis, which still kills far more people than it should, given the increased efficacy of treatment and preventive regimens (see chapter 16). However, the burden of other acute and chronic adult respiratory diseases, which is the focus of this chapter, has been rising throughout the world. These diseases fall into four categories: acute diseases, such as pneumonia and influenza; chronic diseases, such as chronic obstructive pulmonary disease (COPD) and asthma; occupational lung diseases, such as byssinosis, asbestosis, and coal worker's pneumoconiosis; and other parenchymal lung diseases, such as immune-related lung diseases. Lung cancer, tuberculosis, and AIDS-related lung diseases are dealt with in chapters 29, 16, and 18, respectively.
01/2006; , ISBN: 0821361791
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ABSTRACT: Protein tyrosine phosphatase-sigma (PTP-sigma) is a member of the mammalian LAR family of phosphatases, which is characterized by a cell adhesion-like ectodomain, a single transmembrane segment, and two tandemly repeated intracellular catalytic domains. The expression of PTP-sigma is developmentally regulated in epithelial, neuronal, and neuroendocrine tissues. We previously showed that PTP-sigma is strongly expressed within the fetal, but not adult, rat lung and is localized to the Clara cells and type II pneumocytes. In view of the developmentally regulated pulmonary expression of PTP-sigma, we performed a detailed histological and ultrastructural study of the lungs of PTP-sigma knockout mice we have generated. Our findings indicate no apparent structural abnormalities in the lungs of PTP-sigma-/- mice, including airway and alveolar epithelium. In addition, pulmonary neuroendocrine cells also appear normal, in contrast to pituitary, pancreatic, and gastrointestinal endocrine cells, in the knockout mice, suggesting different developmental regulation of these neuroendocrine cells. These observations suggest compensation for the absence of PTP-sigma during development by related family member phosphatases, such as LAR.
AJP Lung Cellular and Molecular Physiology 02/2003; 284(1):L214-23. · 3.66 Impact Factor
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ABSTRACT: Protein tyrosine phosphatase sigma (PTPsigma) is a member of the LAR family of receptor tyrosine phosphatases and is highly expressed in the nervous system during development. PTPsigma is homologous to the Drosophila DLAR, which plays a key role in the targeting of axonal growth cones in flies. We have previously inactivated the Ptprs gene in mice and demonstrated stunted growth, developmental delays, and neurological and neuroendocrine defects in the PTPsigma null animals. Here, we mapped the expression of the lac-Z reporter gene included in the knockout cassette and surveyed the development of the CNS in these mice after birth. The strongest expression of beta-galactosidase (PTPsigma) was observed in the hippocampus, cerebral cortex, olfactory bulbs, and subependymal layer. Our analysis reveals hippocampal dysgenesis, reductions in the thickness of the corpus callosum and the cerebral cortex, and late expression of the growth-associated protein 43 (GAP-43) in the knockout animals. Architectural abnormalities in the brain and spinal cord were confirmed by immunoreactivity to neurofilament and glial fibrillary acidic protein (GFAP) antibodies. Several of these neural abnormalities were corrected with age, suggesting a delay in neurological development related to the knockout of the Ptprs gene. These data suggest that PTPsigma is likely involved in neurogenesis, axonal growth, and axonal pathfinding in the maturation of the mammalian CNS.
Journal of Neuroscience Research 11/2002; 70(1):24-35. · 2.74 Impact Factor
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ABSTRACT: The receptor protein tyrosine phosphatase sigma (PTPsigma) is a member of the mammalian leukocyte common antigen-related (LAR) family. Its expression is developmentally regulated in neuronal tissues. The Drosophila homolog of the mammalian LAR family of phosphatases (DLAR) controls axon guidance during Drosophila embryogenesis. We have demonstrated previously that mice deficient in PTPsigma have CNS and peripheral nervous system abnormalities. The sciatic nerve in the PTPsigma(-/-) mice demonstrates an increased number of small diameter fibers and slower nerve conduction velocities compared with PTPsigma(+/+) or PTPsigma(+/-) controls. To study whether peripheral nerve regeneration is affected by PTPsigma activity, we assessed nerve regeneration in the PTPsigma(-/-) mouse after three standard models of sciatic nerve injury. We report that after sciatic nerve crush injury, nerve regeneration was significantly faster in the PTPsigma(-/-) animals, as determined by histologic, electrophysiologic, and neuromuscular testing. After sciatic nerve transection with immediate microsurgical repair or allografting, PTPsigma(-/-) nerve fibers demonstrated errors in directional growth compared with controls. We propose that PTPsigma regulates the axonal regeneration rate and guidance of regenerating fibers.
Journal of Neuroscience 08/2002; 22(13):5481-91. · 7.11 Impact Factor
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ABSTRACT: The expression of receptor protein tyrosine phosphatase sigma (PTPfinal sigma) is developmentally regulated in neuronal and neuroendocrine tissues. We have previously shown that mice deficient in PTPfinal sigma demonstrate nervous system abnormalities, pituitary hypoplasia, increased neonatal mortality (60%), and death from a wasting syndrome at 2-3 wk of age (38%). We have now examined the role of PTPfinal sigma on pituitary, pancreas and enteroendocrine cytodifferentiation, hormone production, and development. The adenohypophyses of PTPfinal sigma(-/-) mice were small and exhibited reduced GH and PRL immunoreactivity. Cells containing TSH, LH, FSH, ACTH, pituitary-specific POU homeodomain factor (Pit-1), ER, and steroidogenic factor 1 were found in normal proportions and distributions. The diminished expression of GH and PRL was not associated with apoptosis of somatotrophs or lactotrophs. Pit-1-positive TSH-negative cells were detected, suggesting that impaired GH and PRL synthesis was not attributable to Pit-1 deficiency. In the knockout mice, pancreatic islets were hypoplastic with reduced insulin immunoreactivity, and there was also variable expression of gut hormones. Functionally, the GH deficiency was associated with hypoglycemia and death in the PTPfinal sigma(-/-) neonate and accordingly, ip administration of GH rescued the PTPfinal sigma(-/-) neonate and normalized the blood glucose. These data indicate that PTPfinal sigma plays a major role in differentiation and development of the neuroendocrine system.
Molecular Endocrinology 02/2002; 16(1):155-69. · 4.54 Impact Factor
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ABSTRACT: To evaluate and compare thin section CT scans (TSS) and minimum intensity projection images (MinIPs) in healthy individuals, 10 nonsmokers with normal pulmonary function tests were studied using ten 1-mm collimated, helically acquired TSS images after full inspiration and expiration at two anatomic levels. Ten-millimeter-thick MinIPs were generated from the helical scans. Two thoracic radiologists compared TSS and MinIPs for artifacts and air trapping. Hounsfield unit (HU) measurements of TSS and MinIPs were obtained. The lung parenchyma on MinIPs demonstrates a smooth anterior-to-posterior attenuation gradient, accentuated by expiration. Motion and beam-hardening artifacts on TSS images resulted in regions of high and low attenuation on MinIPs, respectively. Expiratory TSS and MinIPs demonstrated air trapping (n = 31/40; range, 0-25%; mean, 7.2%). In comparison with TSS, MinIPs improved the conspicuity of air trapping (n = 20) and appeared to detect more air trapping (n = 7). No statistical differences were found when comparing the mean HU values of TSS and MinIPs. MinIPs demonstrated a smooth anterior-to-posterior attenuation gradient. Compared with TSS, MinIPs improve the conspicuity of air trapping in healthy individuals. Therefore, expiratory MinIPs may be useful in detecting air trapping as a result of disease.
Journal of Thoracic Imaging 02/2002; 17(1):47-52. · 0.98 Impact Factor
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ABSTRACT: The LAR family protein tyrosine phosphatases (PTPs), including LAR, PTPδ, and PTPς, are transmembrane proteins composed of a cell adhesion molecule-like ectodomain and two cytoplasmic catalytic domains: active D1 and inactive D2. We performed a yeast two-hybrid screen with the first catalytic domain of PTPς (PTPς-D1) as bait to identify interacting regulatory proteins. Using this screen, we identified the second catalytic domain of PTPδ (PTPδ-D2) as an interactor of PTPς-D1. Both yeast two-hybrid binding assays and coprecipitation from mammalian cells revealed strong binding between PTPς-D1 and PTPδ-D2, an association which required the presence of the wedge sequence in PTPς-D1, a sequence recently shown to mediate D1-D1 homodimerization in the phosphatase RPTPα. This interaction was not reciprocal, as PTPδ-D1 did not bind PTPς-D2. Addition of a glutathione S-transferase (GST)–PTPδ-D2 fusion protein (but not GST alone) to GST–PTPς-D1 led to ∼50% inhibition of the catalytic activity of PTPς-D1, as determined by an in vitro phosphatase assay against p-nitrophenylphosphate. A similar inhibition of PTPς-D1 activity was obtained with coimmunoprecipitated PTPδ-D2. Interestingly, the second catalytic domains of LAR (LAR-D2) and PTPς (PTPς-D2), very similar in sequence to PTPδ-D2, bound poorly to PTPς-D1. PTPδ-D1 and LAR-D1 were also able to bind PTPδ-D2, but more weakly than PTPς-D1, with a binding hierarchy of PTPς-D1>>PTPδ-D1>LAR-D1. These results suggest that association between PTPς-D1 and PTPδ-D2, possibly via receptor heterodimerization, provides a negative regulatory function and that the second catalytic domains of this and likely other receptor PTPs, which are often inactive, may function instead to regulate the activity of the first catalytic domains.
