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Acute lung injury by endotoxin-induced mediators: prevention by HWA 138, a new xanthine derivative
1Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.
Abstract:
We attempted to mimic septic conditions in vitro by using a model of isolated perfused rabbit lung (IPRL) and evaluated the effects of endotoxin or endotoxin-induced mediators (or both) on it. Moreover, we determined the salutary effects of HWA 138, a new xanthine derivative, against endotoxin-related lung injury. To study this, heparinized human blood was centrifuged, following which the plasma complement was inactivated by heat treatment and the isolated and washed buffy coat cells were then added to it. This was followed by incubation of aliquot suspension with and without endotoxin (lipopolysaccharide [LPS], 100 ng/ml) at 37 degrees C for 2 hours. Plasma was then harvested and is referred to as sepsis-like plasma (SLP). Control plasma (CP) was not exposed to LPS. IPRLs were then perfused with SLP, CP, LPS itself, or both LPS and CP without additional white blood cells. Endotoxin itself did not induce any changes in the presence or in the absence of control plasma; however, sepsis-like plasma led to the development of lung edema, as evidenced by significantly elevated lung water and pulmonary artery pressure. Administration of HWA 138 before the addition of SLP prevented the SLP-induced lung injury. These results lead us to conclude that lung injury is caused by LPS-induced mediators rather than being directly caused by LPS. The results also suggest that HWA 138 may be a useful agent in the treatment of sepsis-induced pulmonary injury.
Insights
Sepsis-like plasma, not endotoxin alone, caused lung injury in a rabbit model. A new xanthine derivative, HWA 138, effectively protected against this sepsis-induced lung injury, suggesting its therapeutic potential.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Toxicology
Background:
- Sepsis can lead to acute lung injury.
- The precise mechanisms of endotoxin-induced lung damage are not fully understood.
- Investigating novel therapeutic agents for sepsis is crucial.
Purpose of the Study:
- To establish an in vitro model of sepsis-induced lung injury using isolated perfused rabbit lungs (IPRL).
- To evaluate the effects of endotoxin and sepsis-like plasma on lung function.
- To assess the protective efficacy of HWA 138, a xanthine derivative, against endotoxin-related lung injury.
Main Methods:
- Human blood was processed to create sepsis-like plasma (SLP) by incubating buffy coat cells with lipopolysaccharide (LPS).
- IPRLs were perfused with SLP, control plasma (CP), LPS, or LPS with CP.
- Lung water and pulmonary artery pressure were measured to assess lung injury.
- The effect of HWA 138 on SLP-induced injury was evaluated.
Main Results:
- Sepsis-like plasma significantly increased lung water and pulmonary artery pressure, indicating lung edema and injury.
- Endotoxin alone did not cause significant lung changes in the IPRL model.
- Pre-administration of HWA 138 prevented the lung injury induced by sepsis-like plasma.
Conclusions:
- Sepsis-induced lung injury in this model is mediated by endotoxin-induced factors in plasma, not directly by endotoxin itself.
- HWA 138 demonstrates significant protective effects against sepsis-related pulmonary injury.
- HWA 138 shows promise as a potential therapeutic agent for treating sepsis-induced lung injury.