Abstract Introduction Studies indicate that mechanically ventilated patients develop significant diaphragm muscle weakness, but the etiology of weakness and its clinical impact remain incompletely understood. We assessed strength in medical ICU patients, correlated development with multiple parameters, examined relationship between level patient outcomes. Methods Transdiaphragmatic twitch pressure (PdiTw) response to bilateral magnetic stimulation phrenic nerves was measured. Diaphragm...

Sepsis elicits severe alterations in cardiac function, impairing mitochondrial and pressure-generating capacity. Currently, there are no therapies to prevent sepsis-induced dysfunction. We tested the hypothesis that administration of a mitochondrially targeted antioxidant, 10-(6'-ubiquinonyl)-decyltriphenylphosphonium (MitoQ), would endotoxin-induced reductions contractile function. Studies were performed on adult rodents (n = 52) given either saline, endotoxin (8 mg x kg(-1) day(-1)),...

Despite treatment advances for sepsis and pneumonia, significant improvements in outcome have not been realized. Antiplatelet therapy may improve pneumonia sepsis. In this study, the authors show that ticagrelor reduced leukocytes with attached platelets as well inflammatory biomarker interleukin (IL)-6. Pneumonia patients receiving required less supplemental oxygen lung function tests trended toward improvement. Disruption of P2Y12 receptor a murine model protected against response,...

Section:ChooseTop of pageAbstract <<Materials and MethodsResultsDiscussionReferencesCITING ARTICLES

Contraction-induced respiratory muscle fatigue and sepsis-related reductions in force-generating capacity are mediated, at least part, by reactive oxygen species (ROS). The subcellular sources mechanisms of generation ROS these conditions incompletely understood. We postulated that the physiological changes associated with contraction (i.e., increases calcium ADP concentration) stimulate mitochondrial a phospholipase A(2) (PLA(2))-modulated process sepsis enhances upregulating PLA(2)...

This study test the hypothesis that a temporal relationship exists between production of superoxide anion (O2 −) and contractile activity perfused rat diaphragm. O2 − levels were determined minute to by measuring reduction cytochrome c in perfusate as diaphragms subjected various activity. After equilibrating at low rates (one 500 ms 80 Hz train/min), fatigued increasing their for 5 min train/s) then allowed recover 30 train/min). During equilibration, did not produce above background level...

Sepsis significantly alters skeletal muscle mitochondrial function, but the mechanisms responsible for this abnormality are unknown.We postulated that endotoxin elicits specific changes in electron transport chain proteins produce derangements function. To examine issue, we compared effects of endotoxin-induced sepsis on ATP (adenosine triphosphate) formation and protein composition.Diaphragm oxygen consumption nicotinamide adenine dinucleotide, reduced form, oxidase assays were measured...

The cecal ligation perforation (CLP) model of sepsis is known to induce severe diaphragm dysfunction, but the cellular mechanisms by which this occurs remain unknown. We hypothesized that CLP induces caspase-3 and calpain activation, these two enzymes act at level contractile proteins reduce muscle force generation. Rats (n = 4/group) were subjected 1) sham surgery plus saline (intraperitoneal); 2) CLP; 3) administration inhibitor peptide III (12 mg/kg ip); or 4) a caspase inhibitor,...

Infections produce significant respiratory muscle weakness, but the mechanisms by which inflammation reduces force remain incompletely understood. Recent work suggests that caspase 3 releases actin and myosin from contractile protein lattice, so we postulated infections may reduce skeletal activating 3. The present experiments were designed to test this hypothesis determining 1) diaphragm activation in after endotoxin 2) effect of a broad-spectrum inhibitor,...

Doxorubicin is a chemotherapeutic agent prescribed for variety of tumors. While undergoing treatment, patients exhibit frequent symptoms that suggest respiratory muscle weakness. Cancer can receive doxorubicin chemotherapy through either intravenous (IV) or intraperitoneal (IP) injections. We hypothesized function would be depressed in murine model chemotherapy. tested this hypothesis by treating C57BL/6 mice with clinical dose (20 mg/kg) via IV IP injection. Three days later we measured...

Recent work indicates that respiratory muscles generate superoxide radicals during contraction (M. B. Reid, K. E. Haack, M. Francik, P. A. Volberg, L. Kabzik, and S. West. J. Appl. Physiol. 73: 1797-1804, 1992). The intracellular pathways involved in this process are, however, unknown. purpose of the present study was to test hypothesis contraction-related formation reactive oxygen species (ROS) by skeletal muscle is linked activation 14-kDa isoform phospholipase A(2) (PLA(2)). Studies were...

Reactive oxygen species contribute to diaphragm dysfunction in certain pathophysiological conditions (i.e., sepsis and fatigue). However, the precise alterations induced by reactive or specific that are responsible for derangements skeletal muscle function incompletely understood. In this study, we evaluated effect of superoxide anion radical (O 2 − ·), hydroxyl (·OH), hydrogen peroxide (H O ) on maximum calcium-activated force (F max calcium sensitivity contractile apparatus chemically...

Peroxynitrite may be generated in and around muscles several pathophysiological conditions (e.g., sepsis) induce muscle dysfunction these disease states. The effect of peroxynitrite on force generation has not been directly assessed. purpose the present study was to assess effects administration diaphragmatic force-generating capacity 1) intact diaphragm fiber bundles (to model produced by exposure extracellular peroxynitrite) 2) single skinned fibers intracellular contractile protein...

Cellular energy metabolism is altered in sepsis as a consequence of dysfunction mitochondrial electron transport and glycolytic pathways. The purpose the present study was to determine whether associated with compensatory increases gene expression chain pathway proteins or, alternatively, decreases sepsis, contributing abnormalities metabolism. Studies were performed using diaphragms from control endotoxin-treated (8 mg·kg −1 ·day ) rats; at 48 h after endotoxin administration, animals...

Infections produce severe respiratory muscle dysfunction. It is known that the proteasome proteolytic system activated in skeletal sepsis, and it has been postulated this degradative pathway responsible for inducing weakness wasting. The objective of study was to determine if administration proteasomal inhibitors (MG132, epoxomicin, bortezomib) can prevent sepsis-induced diaphragm weakness. Rats were given either 1) saline (0.5 ml ip), 2) endotoxin (12 mg/kg 3) plus MG132 (2.5 mg/kg), 4)...

A major consequence of ICU-acquired weakness (ICUAW) is diaphragm weakness, which prolongs the duration mechanical ventilation. Hyperglycemia (HG) a risk factor for ICUAW. However, mechanisms underlying HG-induced respiratory muscle are not known. Excessive reactive oxygen species (ROS) injure multiple tissues during HG, but only one study suggests that excessive ROS generation may be linked to weakness. We hypothesized dysfunction mediated by superoxide and administration specific...

Respiratory muscle weakness contributes to respiratory failure in ICU patients. Unfortunately, assessment of is difficult since the most objective test, transdiaphragmatic pressure response phrenic nerve stimulation (PdiTw), perform. While clinicians utilize maximum inspiratory (Pimax) assess strength, relationship this index PdiTw has not been evaluated a large population. The purpose present study was both and Pimax patients determine how these indices correlate with each other, what...

Multiple factors contribute to exercise intolerance in patients with sickle cell anemia, but little information exists regarding the safety of maximal cardiopulmonary testing (CPET) or mechanisms limitation these patients. The purpose present study was examine issues. Seventeen adult women anemia underwent symptom-limited CPET using cycle ergometry and ramp protocols; blood gases lactate concentrations were measured every 2 minutes. All completed without complications. No patient...

Rationale: Sepsis produces significant mitochondrial and contractile dysfunction in the heart, but role of superoxide-derived free radicals genesis these abnormalities is not completely understood.Objectives: The study was designed to test hypothesis that superoxide scavenger administration prevents endotoxin-induced cardiac dysfunction.Methods: Four groups rats were studied, animals injected with either saline, endotoxin, endotoxin plus polyethylene glycol-adsorbed–superoxide dismutase...

Calpain activation occurs in skeletal muscle response to infection, but it is unknown if calpain inhibition improves functional capacity. We hypothesized that infection induces diaphragm activation, results cleavage of important cytoskeletal proteins, and attenuates infection-induced dysfunction. Mice (n = 4-6/group) were given: (1) saline (intraperitoneal); (2) endotoxin (12 mg/kg intraperitoneal); (3) inhibitor peptide III (4) mg/kg) plus mg/kg). At 24 hours, diaphragms removed the...