Chao T J, Chou C L, Hsu K, Wang D
Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan, Republic of China.
Chin J Physiol. 1990;33(4):301-14.
A good model of adult respiratory distress syndrome is lung injury induced by phorbol myristate acetate (PMA). In the present study we examined the effect of mepacrine, an inhibitor of phospholipase A2, on lung injury induced by PMA in isolated blood-perfused rat lungs. In the isolated lung, saline (1 ml) or mepacrine (75 microM) alone in the perfusion system did not discernibly change the pulmonary arterial pressure (PAP) and lung weight (LW). After administration of PMA (0.16 micrograms/ml), severe hypertension and lung edema developed (delta PAP = 40.1 +/- 6.0 mmHg, p less than 0.001; delta LW = 5.5 +/- 0.7 g, p less than 0.001). Whereas, the addition of mepacrine (75 microM) prevented PMA-induced lung edema and pulmonary hypertension (delta PAP = 4.7 +/- 2.2 mmHg, delta LW = 0.2 +/- 0.2 g). To further elucidate the protective mechanism of mepacrine on lung injury, a vasodilator (nitroprusside) was given to decrease PAP levels to +6 mmHg from baseline values in the PMA group, as well as in the mepacrine-pretreated PMA (MPMA) group. During a subsequent venous pressure challenge, severe lung injury developed in the PMA group (delta LW = 9.5 +/- 2.1 g, p less than 0.001). However, with the same venous pressure challenge in the MPMA the lung weight was markedly less than that of the PMA group (delta LW = 1.0 +/- 0.2 g). Histologic findings examined by light microscopy presented intraalveolar hemorrhage and fluid accumulation, disruption of vascular basements and alveolar septa, and aggregation of inflammatory cells within the parenchyma in the lungs of the PMA group. In the MPMA group there was no evidence of intraalveolar hemorrhage and alveolar fluid accumulation, however, the occasional presence of granulocytes in the parenchyma and slight interstitial edema were still observed. In addition, depressed the chemiluminescence release from PMA activated granulocytes which were in a dose-dependent manner in vitro. These observations suggest that mepacrine inhibits PMA-induced lung injury chiefly by protection of vascular permeability. The mechanism of the protection may be due to the inhibition of oxygen radicals released from activated neutrophils and the reduction of neutrophil chemotaxis.
成人呼吸窘迫综合征的一个良好模型是由佛波酯（PMA）诱导的肺损伤。在本研究中，我们研究了磷脂酶A2抑制剂米帕林对PMA诱导的离体血液灌注大鼠肺损伤的影响。在离体肺中，灌注系统中单独使用生理盐水（1毫升）或米帕林（75微摩尔）对肺动脉压（PAP）和肺重量（LW）没有明显影响。给予PMA（0.16微克/毫升）后，出现严重高血压和肺水肿（ΔPAP = 40.1±6.0毫米汞柱，p<0.001；ΔLW = 5.5±0.7克，p<0.001）。然而，添加米帕林（75微摩尔）可预防PMA诱导的肺水肿和肺动脉高压（ΔPAP = 4.7±2.2毫米汞柱，ΔLW = 0.2±0.2克）。为了进一步阐明米帕林对肺损伤的保护机制，给予血管扩张剂（硝普钠）将PMA组以及米帕林预处理的PMA（MPMA）组的PAP水平从基线值降至+6毫米汞柱。在随后的静脉压挑战期间，PMA组出现严重肺损伤（ΔLW = 9.5±2.1克，p<0.001）。然而，在MPMA组中进行相同的静脉压挑战时，肺重量明显低于PMA组（ΔLW = 1.0±0.2克）。通过光学显微镜检查的组织学结果显示，PMA组肺内有肺泡内出血和液体蓄积、血管基底膜和肺泡间隔破坏以及实质内炎症细胞聚集。在MPMA组中，没有肺泡内出血和肺泡液体蓄积的证据，然而，仍观察到实质内偶尔有粒细胞存在和轻微间质水肿。此外，米帕林在体外以剂量依赖的方式抑制PMA激活的粒细胞的化学发光释放。这些观察结果表明，米帕林主要通过保护血管通透性来抑制PMA诱导的肺损伤。保护机制可能是由于抑制活化中性粒细胞释放的氧自由基和减少中性粒细胞趋化性。
