Modulation of Ischemic Lung Injury by Corticosteroids

Perng

et al. 2000

Clinical Science

The choice of an intravenous solution for the attenuation of ischaemia/reperfusion (I/R) lung injury is still a difficult one. Although 10% (w/v) pentastarch has been used in ICU settings, its use in I/R lung injury has not been well explored. We hypothesized that this synthetic colloid substance, which maintains colloid osmotic pressure and potentially 'seals' capillary leaks, in combination with an anti-inflammatory agent (i.e. dexamethasone), would ameliorate I/R lung injury. After 60 min of lung ischaemia in an isolated rat lung model, lungs were reperfused for 60 min in a closed circulating system with one of the following solutions: (1) NS (0.9% normal saline), (2) NS+Dex (dexamethasone), (3) NS+Penta (pentastarch), or (4) NS+Penta+Dex. Haemodynamic changes, lung weight gain (LWG), capillary filtration coefficient (K(fc)) and lung pathology were analysed. Results showed significantly lower values of K(fc) and LWG in pentastarch- or dexamethasone-perfused groups as compared with those in the NS group. Dexamethasone as an additive to NS+Penta further decreased K(fc) and LWG. Histopathological studies showed similar decreases in injury profiles. We conclude that reperfusion with dexamethasone and pentastarch can attenuate I/R lung injury, and that dexamethasone and pentastarch have additive effects. Our data thus suggest that the combination of a colloid substance with 'sealing effects' and an anti-inflammatory agent may provide a better reperfusion solution for patients with I/R lung injury or for lungs stored for transplant.

Section: Discussionmentioning

confidence: 82%

Dexamethasone and pentastarch produce additive attenuation of ischaemia/reperfusion lung injury

Perng

et al. 2000

Clinical Science

“…and Bt # -cAMP were not evaluated in our study, but it is known that : (1) Dex, a phospholipase A # inhibitor, suppresses neutrophil function and cytokine production and reduces the formation of leukotrienes [28,29] ; (2) PGE " causes vasodilatation [30,31], bronchodilation [32], less aggregation of platelets and leucocytes [31], the suppression of TNF [7,33], immunosuppression [33][34][35], and produces a variety of ' cyto-protective ' effects [36][37][38]. In an orthotopic rat lung transplant model, Naka et al [39] showed that vasodilatation alone is insufficient to enhance lung preservation and that PGE " promotes lung preservation by stimulating cAMP-dependent protein kinase and promoting non-vasodilatory mechanisms of pulmonary protection.…”

Section: Discussionmentioning

confidence: 99%

Protective agents used as additives in University of Wisconsin solution to promote protection against ischaemia–reperfusion injury in rat lung

et al. 1998

Clinical Science

1. An intervention to reduce ischaemia-reperfusion lung injury will be an important advance in transplant medicine. Although the mechanisms associated with producing ischaemia-reperfusion endothelial injury have not been completely elucidated, many of the injury mediators have been studied in detail. While no single pharmacological therapy is likely to be totally effective in eliminating this complex injury, we have developed a mixture of agents that are known to block pathways involved in producing ischaemia-reperfusion-associated lung vascular injury.2. The present study modified University of Wisconsin solution (UW) by adding one of the protective agents prostaglandin E1 (PGE1), dexamethasone (Dex) or dibutyryl cAMP (Bt2-cAMP), or a combination of these, to the perfusate of rat lungs exposed to 4 h of cold ischaemia followed by 1 h of reperfusion. Nine modified UW solutions were studied: (1) UW+Dex, (2) UW+PGE1, (3) UW+Bt2-cAMP, (4) UW+Dexx3, (5) UW+PGE1x3, (6) UW+Bt2-cAMPx3, (7) UW+Dex+PGE1, (8) UW+Dex+Bt2-cAMP, (9) UW+PGE1+Bt2-cAMP. These solutions were utilized in individual experiments to assess haemodynamic changes, lung weight gain, the capillary filtration coefficient (Kfc) and pathology in all lungs.3. The results indicate that lung weight gain and Kfc values were significantly lower than with UW alone in groups 1, 2 and 3, which contained only one additional protective agent. In groups 4, 5 and 6, which contain three times the concentration of each protective agent, both Kfc and lung weight gain were similar to those measured in groups 1, 2 and 3, i.e. lungs were protected but the protection was not dose dependent. In groups 7, 8 and 9, which contained two protective agents, lung weight gain and Kfc were greatly reduced compared with UW alone. Histopathological studies showed similar decreases in the injury profiles of lungs.4. Although UW contains several antioxidant protective agents such as allopurinol and glutathione, it did not provide effective protection in our ischaemia-reperfusion lung injury model. UW modified with an additive of PGE1, Dex or Bt2-cAMP attenuated ischaemia-reperfusion injury. Furthermore, UW containing two of these protective agents augmented the protection. Among the modified solutions, it appears that UW+PGE1+Bt2-cAMP protects the lungs to a greater extent than all other solutions used in our study. We suggest that preservation solutions containing PGE1-Bt2-cAMP will provide additional protective effects to organs stored for transplantation.

“…Substantial literature shows that some of the commonly used protective agents such as prostaglandin E 1 (PGE 1 ), dexamethasone (Dex), dibutyryl-adenosine 38,58-cyclic monophosphate (Bt 2 -cAMP), and U-74389G (an experimental drug of the lazaroid class) have been postulated to exert a positive effect on the reduction of acute lung injury (5,13,18,27,28,36). In this study, we hypothesized that modifications of UW solution by adding protective agents will enhance its protective effects from the acute I/R lung injury.…”

mentioning

confidence: 99%

PGE₁, dexamethasone, U-74389G, or Bt₂-cAMP as an additive to promote protection by UW solution in I/R injury

Journal of Applied Physiology

Hsu

Yan

et al. 1997

A method to reduce ischemia-reperfusion (I/R) injury can be an important criterion to improve the preservation solution. Although University of Wisconsin solution (UW) works as a lung preservation solution, its attenuation effect on I/R injury has not been investigated. We attempted to determine whether, by adding various protective agents, modified UW solutions will enhance the I/R attenuation by UW. We examined the I/R injury in an isolated rat lung model. Various solutions, e.g., physiological salt solution (PSS), UW, and modified UW solutions containing various protective agents such as prostaglandin E1, dexamethasone, U-74389G, or dibutyryl adenosine 3',5'-cyclic monophosphate were perfused individually to evaluate the I/R injury. Isolated rat lung experiments, with ischemia for 45 min, then reperfusion for 60 min, were conducted in a closed circulating system. Hemodynamic changes, lung weight gain (LWG), capillary filtration coefficient (Kfc), protein content of lavage fluid, concentration of cytokines, and lung histopathology were analyzed. Results showed that the acute I/R lung injury with immediate permeability pulmonary edema was associated with an increase in tumor necrosis factor-alpha (TNF-alpha) production. A significant correlation existed between TNF-alpha and Kfc (r = 0.8, P < 0.0001) and TNF-alpha and LWG (r = 0. 9, P < 0.0001), indicating that TNF-alpha is an important cytokine modulating early I/R injury. Significantly lower levels of Kfc, LWG, TNF-alpha, and protein concentration of lung lavage (P < 0.05) were found in the UW-perfused group than in the control group perfused with PSS. Modified UW promoted the protective effect of UW to further decrease Kfc, LWG, and TNF-alpha (P < 0.05). Histopathological observations also substantiated this evidence. In the UW+U-74389G group, bronchial alveolar lavage fluid contained lowest protein concentration. We conclude that the UW solution attenuates I/R injury of rat lung and that the modified UW solutions further enhance the effect of UW in reducing I/R injury. Among modified solutions, UW+U-74389G is the best. Further investigation of the improved effects of the modified UW solutions would be beneficial in lung transplantation.