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Phorbol myristate acetate-induced injury of isolated perfused rat lungs: neutrophil dependence
1Department of Physiology, College of Medicine, University of South Alabama, Mobile 36688.
Abstract:
The effect of leukocyte depletion on acute lung injury produced by intravenous or intratracheal phorbol myristate acetate (PMA) administration was studied in isolated perfused rat lungs. Vascular endothelial permeability was assessed by use of the capillary filtration coefficient (Kf,c). A predicted pulmonary capillary pressure (Ppc,p) was calculated from measurements of postcapillary resistances. These parameters were measured before and 90 min after the administration of PMA, either intratracheally or intravascularly. When blood elements were present both intratracheal and intravascular PMA caused an increased Kf,c [0.27 +/- 0.02 vs. 0.99 +/- 0.22 and 0.25 +/- 0.05 vs. 0.64 +/- 0.15 (SE) ml.min-1.cmH2O-1.100 g-1, respectively; P less than 0.05] and an increased Ppc,p (8.3 +/- 0.4 vs. 74.7 +/- 18.3 and 8.7 +/- 0.8 vs. 74.2 +/- 25.1 cmH2O, respectively; P less than 0.05). Removal of circulating leukocytes abolished the increased Kf,c when PMA was given intratracheally (0.35 +/- 0.06 vs. 0.23 +/- 0.07 ml.min-1.cmH2O-1.100 g-1) or intravascularly (0.39 +/- 0.07 vs. 0.33 +/- 0.07 ml.min-1.cmH2O-1.100 g-1). In the absence of neutrophils, Ppc,p slightly increased with intratracheal PMA, from 6.9 +/- 0.5 to 10.5 +/- 1.1 cmH2O (P less than 0.05), but was unchanged at 90 min with intravascular PMA. Depletion of circulating neutrophils with an antineutrophil serum failed to block the Kf,c change with intratracheal PMA (from 0.24 +/- 0.03 to 0.42 +/- 0.09 ml.min-1.cmH2O-1.100 g-1; P less than 0.05). Ppc,p also increased from 6.9 +/- 0.6 to 19.8 +/- 6.7 cmH2O (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Leukocyte depletion prevents acute lung injury caused by phorbol myristate acetate (PMA). Removing leukocytes significantly reduced vascular endothelial permeability and pulmonary capillary pressure increases following PMA administration in rat lungs.
Area of Science:
- Pulmonary Medicine
- Inflammation Research
- Vascular Biology
Background:
- Acute lung injury (ALI) is a severe condition characterized by increased pulmonary vascular permeability.
- Phorbol myristate acetate (PMA) is a potent activator of inflammatory cells, often used to induce ALI in experimental models.
- The role of leukocytes, particularly neutrophils, in mediating PMA-induced ALI is not fully elucidated.
Purpose of the Study:
- To investigate the effect of leukocyte depletion on ALI induced by PMA.
- To determine whether circulating leukocytes are essential for the development of increased vascular permeability and pulmonary capillary pressure in response to PMA.
- To differentiate the roles of circulating leukocytes versus resident lung cells in PMA-induced ALI.
Main Methods:
- Isolated perfused rat lungs were used to study ALI.
- PMA was administered either intratracheally or intravenously.
- Leukocyte depletion was achieved using specific depletion protocols.
- Vascular endothelial permeability was assessed using the capillary filtration coefficient (Kf,c).
- Pulmonary capillary pressure (Ppc,p) was calculated from postcapillary resistances.
Main Results:
- PMA administration (intratracheal or intravenous) significantly increased Kf,c and Ppc,p in the presence of blood elements.
- Removal of circulating leukocytes abolished the PMA-induced increase in Kf,c via both administration routes.
- In leukocyte-depleted lungs, intratracheal PMA caused a slight increase in Ppc,p, while intravenous PMA did not significantly alter it.
- Depletion of neutrophils using antineutrophil serum did not prevent the Kf,c increase with intratracheal PMA, although Ppc,p increased.
Conclusions:
- Circulating leukocytes play a critical role in mediating acute lung injury and increased vascular permeability induced by PMA.
- While neutrophils contribute to increased pulmonary capillary pressure, other mechanisms may be involved in the initial increase in vascular permeability, particularly with intratracheal PMA.
- Leukocyte depletion is a potential therapeutic strategy for mitigating PMA-induced acute lung injury.