Oxygen sensing, HIF-1alpha stabilization and potential therapeutic strategies.
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Animals↗
Biomedical subjects
H Wenger
Publications and source records attributed to H Wenger.
Influence of concentric resistance training on concentric and eccentric strength.
This study investigated the effects of isokinetic concentric training on isokinetic concentric and eccentric torque outputs. Sixteen female subjects (mean age in years +/- SE = 21 +/- 1) were randomly assigned to either a training or a control group. Concentric and eccentric torques of the right knee extensors were assessed at 1.05rad.s-1 using a KinCom isokinetic dynamometer system. Each test consisted of a set of four maximal concentric and four maximal eccentric contractions of the knee extensors. The peak and average torques for each contraction were calculated using the computer software supplied by the KinCom manufacturer. On a separate day, after abstaining from heavy exercise for at least 12 hours, a single cross-sectional image of the thigh at midfemur was obtained using computer tomography (CT) scanning. From this image, cross-sectional area of the quadriceps femoris group was calculated using the computer software associated with the General Electric 9800 CT Scanning System. Training group subjects trained three days weekly for six weeks on a Cybex II+ isokinetic dynamometer, completing five sets of ten maximal effort knee extensions at an angular velocity of 1.05rad.s-1. Each set of exercise was separated by two minutes of self-selected recovery. Torque outputs were monitored daily to ensure that adequate recovery was provided between sets of exercise, and to document changes in strength as the program progressed. Significant (p less than .01) increases in peak and average concentric torque (11% and 12%, respectively), peak and average eccentric torque (18% and 21%, respectively), and muscle cross-sectional area (3.2%) were observed for training group subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Endotoxin-induced prostanoid production by the burn wound can cause distant lung dysfunction.
We injected Escherichia coli endotoxin, 2 micrograms/kg, beneath the eschar of sheep with 25% total body surface full-thickness burns to determine whether burn tissue in the presence of endotoxin releases prostanoids, particularly thromboxane A2, (TxA2), and if increased local TxA2 production can lead to distant lung dysfunction. We compared this response to the lung injury produced by the same dose given intravenously. We noted a marked increase in burn tissue TxA2 production after subeschar endotoxin as reflected in significant increases in burn lymph and pulmonary artery TxB2 levels. Pulmonary artery pressure increased from 22 to 38 mm Hg and PaO2 decreased from 89 to 71 torr while lung lymph flow (QL) increased only modestly with no evidence of increased lung permeability. The TxA2 production and the lung response were prevented by the subeschar injection of ibuprofen, 12.5 mg/kg. Circulating endotoxin was noted in only one of five sheep. After intravenous (endotoxin), a significant increase in lung TxA2 production was noted and a characteristic two-phase lung injury was seen with an initial phase basically identical to that seen with the subeschar injection followed by an increase in lung protein permeability. Burn tissue endotoxin can stimulate local TxA2 production leading to distant lung dysfunction without the need for circulating endotoxin. The source of the TxA2 is the burn, while with endotoxemia the source is the lung.
Animals↗
Pulmonary dysfunction secondary to soft-tissue endotoxin.
Our purpose was to determine whether peripheral soft tissues produce and release prostanoids in response to local sepsis, and whether this mediator release can produce pulmonary dysfunction. Escherichia coli endotoxin (2 micrograms/kg in 100 mL of saline) was injected below the hide of the flank in seven unanesthetized sheep. In three additional sheep, ibuprofen (12.5 mg/kg of body weight) was injected with the endotoxin. Thromboxane B2 and 6-keto-PGF1 alpha (prostacyclin) levels were measured in tissue lymph draining the flank, lung lymph, pulmonary artery (Ppa), and aortic plasma. One hour after endotoxin administration, mean PaO2 decreased from 90 to 74 mm Hg and Ppa increased from 22 to 35 mm Hg. Lung lymph flow (QL) increased only 50% with QL being protein poor. No increase in lung or peripheral soft-tissue vascular permeability was noted. Tissue lymph (TxB2) increased from 220 +/- 114 to greater than 10,000 pg/mL with levels in Ppa plasma increasing from 300 +/- 128 to 595 +/- 124 pg/mL and aortic plasma from 270 +/- 141 to 410 +/- 104 pg/mL. Lung lymph TxB2 paralleled aortic values. Peak levels of 6-keto-PGF1 alpha in systemic lymph exceeded 2,000 pg/mL while levels in lung lymph remained relatively constant. The pulmonary injury and the increase in TxB2 was prevented by ibuprofen. We conclude that the response of soft tissue to local endotoxin is to release thromboxane in quantities sufficient to raise plasma levels and to produce hypoxia and pulmonary hypertension. The lung dysfunction is not produced by an increase in lung water or vascular permeability.
6-Ketoprostaglandin F1 alpha↗
Chemotactic activity of plasma and lung lymph in sheep with endotoxemia: effect of hydroxyl radical scavengers.
The formation and release of circulating chemoattractants has been considered to be responsible for the initial pulmonary leukostasis and subsequent pulmonary vascular injury seen with endotoxemia. Oxygen radicals released from granulocytes can produce these factors. Our purpose was (1) to determine whether chemotaxins are released with endotoxemia and whether the lung is the source of these factors and (2) if there is a cause and effect relationship between the release of chemoattractants and the lung injury. Lung lymph flow, QL, lymph protein clearance, and vascular pressures were used to monitor lung vascular integrity. Escherichia coli endotoxin was infused into 12 sheep. Six sheep were pretreated with dimethyl thiourea (DMTU), a scavenger of hydroxide ion radicals. Chemotactic activity (CA) of plasma and lung lymph was determined during baseline, the pulmonary hypertensive phase, and the permeability phase of the lung injury. It was found that endotoxemia was associated with generation of a granulocyte chemotactic factor in plasma but not in lung lymph. The peak increase in plasma CA occurred after the early pulmonary leukostasis. Pretreatment with DMTU eliminated the increased CA but had no effect on the initial leukopenia or the lung injury. It was concluded that (1) the lung is not the major source of increased CA after endotoxin and (2) increased plasma CA occurs but does not appear to be causative of the initial pulmonary leukostasis or the granulocyte-induced lung injury.
Animals↗
Effect of a body burn on the lung response to endotoxin.
Our purpose was, in general, to determine the effect of a body burn on the pulmonary response to endotoxemia and, specifically, to determine whether increased thromboxane (TxA2) production by the burn wound was responsible for the accentuated lung injury. Thirty-two unanesthetized sheep with lung and soft tissue lymph fistulae were studied. Twelve sheep were given a sublethal dose of intravenous E. coli endotoxin (2 micrograms/kg). A characteristic two-phase injury was noted as evidenced by early pulmonary hypertension and hypoxia and later increased lung permeability. TxA2 was significantly increased in lung lymph as well as aortic plasma relative to venous plasma, indicating the lung to be the source. Twelve of 12 sheep survived. Five of 13 sheep died from endotoxemia when given 3-5 days after a 25% total body surface (TBS) burn and five of seven died with endotoxin (2 micrograms/kg) and a 50% burn. Physiologic parameters were at preburn levels before endotoxin. Animals died both during the early phase from hypoxia and the later phase due, in large part, to increasing pulmonary dysfunction. Absolute levels of TxA2 were not increased in the postburn animals, nor was there a clear release of TxA2 from burn tissue to explain the accentuated response. Prostacyclin levels were, however, less elevated in postburn animals in response to endotoxin, thereby altering the TxA2/PGI2 ratio in favor of TxA2. However, a cause and effect relationship between the increased lung injury and TxA2 remains undetermined. Lymph flow or lymph protein content was not altered in burn tissue in response to endotoxin.
Animals↗
Role of subcutaneous tissue endotoxin in the production of prostanoid-induced lung injury: comparison with intravenous endotoxin response.
Local injection of endotoxin into soft tissues of the flank results in hypoxia and pulmonary hypertension. Our purpose was to determine whether this was caused by tissue prostanoid production or production by the lung as is seen with endotoxemia. Twenty-six sheep were prepared with lung and flank tissue lymph fistulae. Thirteen sheep were given 2 micrograms/kg Escherichia coli endotoxin into the flank soft tissue, six of which were pretreated with ibuprofen, 12.5 mg/kg. Thirteen sheep were given intravenous endotoxin, 2 micrograms/kg, with six pretreated with ibuprofen. An early hypertensive phase was noted with both insults characterized by pulmonary hypertension, hypoxia, and increased lung lymph flow (QL). With subcutaneous tissue endotoxin, there was a significant increase in tissue lymph TxB2 and 6-keto-PGF1 alpha when compared to lung lymph and increased values in venous plasma compared to arterial plasma, indicating tissue to be the source. With intravenous endotoxin, lung lymph and aortic plasma levels were significantly higher than tissue lymph and venous plasma, respectively. The hypoxia, hypertension and increased prostanoids were prevented using ibuprofen. An increased lung permeability phase was noted with intravenous endotoxin but not with tissue endotoxin. As expected, this phase was not inhibited with ibuprofen and, therefore, not prostanoid-induced.
6-Ketoprostaglandin F1 alpha↗
Effect of endotoxin on the integrity of the peripheral (soft tissue) microcirculation.
Peripheral edema, hypoproteinemia, and increased fluid requirements are characteristically seen with sepsis. Our purpose was to determine whether the soft tissue edema is caused by a direct vascular injury from sepsis or is secondary to hypoproteinemia. We determined the effect of endotoxin on peripheral (soft tissue) microvascular integrity using lymph flow (QL) and lymph/plasma (L/P) protein ratio to reflect fluid flux and increased permeability. Response was compared with that seen in the lung. Fourteen unanesthetized sheep were given intravenous E. coli endotoxin 2 micrograms/kg. Vascular pressures and cardiac output (CO) were maintained constant with the necessary fluid infusion. Lung QL increased two- to fourfold in all animals with lymph being protein-rich, indicating increased permeability. Peripheral QL increased transiently in response to an initial increase in vascular pressure returning rapidly to baseline except in those animals (N = 5) demonstrating hypoproteinemia where QL remained increased by 50 to 75%. The increased QL was totally explained by the degree of protein depletion, with no evidence of increased permeability. To assure an adequate endotoxin exposure to the peripheral microvessels, endotoxin (2 micrograms/kg) was also directly injected into the tissue drained by the soft tissue lymphatic. We noted a characteristic endotoxin pulmonary hypertension phase but, again, no increase in peripheral microvascular permeability was found. We conclude that endotoxemia does not alter peripheral microvascular permeability if tissue perfusion is maintained, while the lung is clearly a target organ. Hypoproteinemia may be responsible for the early edema in soft tissues with sepsis.
Animals↗
Myofibril and sarcoplasmic reticulum changes with exercise and growth.
The intent of this study was to observe the effects of different treadmill running programs upon selected biochemical properties of soleus muscle from young rats. Young 10 day litter-mates were assigned to endurance (E), spring (S) and control (C) groups. Each was partitioned into either 21 or 51 day exercising groups and 10 day controls. For C the myofibril ATPase activity at 21 and 51 days were lower than 10 day activity (p less than or equal to 0.05). In the 51 day E group ATPase activity (0.378 +/- 0.009 mumol Pi X mg-1 X min-1) was greater than at 10 and 21 days (0.307 +/- 0.006 and 0.323 +/- 0.008 mumol Pi X mg-1 X min-1) (p less than or equal to 0.05). No change occurred in the S group from 10 to 21 and 51 days (p greater than or equal to 0.05). Both the 21 and 51 day S (0.318 +/- 0.011 and 0.399 +/- 0.010 mumol Pi X mg-1 X min-1) and E (0.323 +/- 0.008 and 0.378 +/- 0.009 mumol Pi X mg-1 X min-1) groups had higher activity compared to the C group (0.193 +/- 0.029 and 0.172 +/- 0.031 mumol Pi X mg-1 X min-1) (p less than or equal to 0.05). Maturation (10--51 day) resulted in a lowered sarcoplasmic reticulum (SR) yield and Ca2+ binding (p less than or equal to 0.05) while Ca2+ uptake ability did not change (p greater than or equal to 0.05). SR yield, Ca2+ binding and uptake were not altered with S training (p greater than or equal to 0.05). The E training resulted in greater Ca2+ uptake at 51 days compared to C and S (p less than or equal to 0.05), with no change in Ca2+ binding (p greater than or equal to 0.05). The data suggest that E training alters the normal development pattern of young rat soleus muscle.
Adenosine Triphosphatases↗
Functional overload of rat fast-twitch skeletal muscle during development.
The intent of this study was observe the effects of different training programs on selected biochemical properties in lantaris muscle of young rats. Littermates (10 days old) were assigned to endurance (E), sprint (S), and control (C) groups. Animals in each group were partitioned into either 21- or 51-day groups and 10-day controls. Myofibrillar ATPase activities at 21 and 51 days (0.720 +/- 0.028 and 0.719 +/- 0.012 mumol Pi.mg-1.min-1) were higher than the 10-day activity (0.191 +/- 0.022 mumol Pi.mg-1.min) for C animals (P less than or equal to 0.05). At 51 days, E training resulted in a lower ATPase activity than both the 21-day E and 51-day C animals (P less than or equal to 0.05). Sarcoplasmic reticulum protein yield and Ca2+ binding and uptake increased from 10 to 51 days for C animals (P less than or equal to 0.05). The Ca2+-binding ability for 51-day E animals (26.1 +/- 3.4 nmol Ca2+/mg) was greater than for the 51-day C animals (20.0 +/- 1.69 nmol Ca2+/mg) (P less than or equal to 0.05). The plantaris muscle of S animals were not altered at 21 and 51 days compared to C animals were not altered at 21 and 51 days compared to C animals (all variables). The results suggest that exercise training alters the biochemical characteristics of skeletal muscle during growth.
Adenosine Triphosphatases↗