Acute lung failure induced by tricyclic antidepressants : an experimental evaluation

Abstract

The tricyclic antidepressant drugs (TCA) have, over the years, been reported to be able to cause adult respiratory distress syndrome (ARDS)/acute lung injury in connection with overdose, and are currently among the most common cause of self-poisoning. Approximately 10% of all TCA overdose patients develop ARDS, and the treatment of these patients, irrespective of the event causing ARDS, is mainly supportive. Moreover, the mechanisms behind ARDS induction are not entirely clear.

In view of this, we wanted to study if TCA caused ARDS-like symptoms in an isolated perfused and ventilated lung model, and if so, to define which mediators that could be involved. Amitriptyline, a TCA, caused a dose-dependent, rapid and pronounced vaso- and bronchoconstriction in the isolated rat lung. Morphological studies revealed endothelial damage and edema formation in lungs exposed to high amitriptyline concentrations.

Moreover, the release of the potent vaso- and bronchoconstrictive peptide endothelin-1 (ET-1) was observed in amitriptyline-exposed lungs, and exogenously administered ET-1 caused similar effects as amitriptyline in the isolated lung, namely rapid vaso- and bronchoconstriction. This suggests ET-1 to be an important mediator in amitriptyline- induced lung injury. ET-1 has also been reported to be involved in ARDS and endothelin receptor antagonists could partly block the lung function impairment caused by ET-1. Pretreatment with the combined ETA/ETB specific antagonist PD145065 or the ETA-specific receptor antagonist BQ-123 attenuated the ET-1-induced vasoconstriction. The protein kinase inhibitor staurosporine also blocked the vasoconstriction. However, endothelin antagonists, protein kinase inhibitors or the calcium channel blocker verapamil did not affect ET-1-induced bronchoconstriction.

We hypothesised that the vascular endothelium and thereby the endothelial cell was the primary target cell for the TCAs in our lung model. To more closely look at effects on this cell type as well as smooth muscle cells, in vitro studies on human umbilical vein endothelial (HUVE) and smooth muscle (HUVSM) cells were conducted. Studies concerning toxicity and membrane fluidity, as well as cell layer permeability were performed and the results demonstrated that, at sub-toxic concentrations, amitriptyline caused a decreased electrical resistance over a HUVE/HUSM co-culture system, reflecting an increased cellular permeability, probably due to loss of tight junction integrity. This could be connected to the edema observed in ARDS patients as well as in our isolated lung model. Additional in vitro experiments also indicated that amitriptyline caused an increase in intracellular calcium levels, and this is known to affect tight junction function.

To investigate additional mediators/mechanisms which could be involved in the physiological responses of the lung to amitriptyline, studies in which we tried to protect isolated lungs from amitriptyline-induced lung function impairment were conducted. A variety of different substances were tested and our results proposed the involvement of ET-1, platelet activating factor (PAF) and protein kinases.

Altogether, our studies indicate that ET-1 is one important mediator of amitriptyline-induced pulmonary responses. Moreover, the lung damage induced by TCA/amitriptyline in many ways resembles the features of more established experimental ARDS models as well as the clinical picture. The isolated perfused lung model, with amitriptyline as initiating agent for acute lung injury, may therefore be a useful method for study of drug-induced ARDS as well as ARDS in general.