The shortage of donor organs is one of the most important problems of modern clinical transplantation. Among the organs typically obtained from deceased donors, the situation with pulmonary transplantation is particularly alarming. Expansion of indications for lung transplantation procedure combined with early morbidity and mortality and high incidence of chronic rejection following transplantation resulted in rapidly growing waiting lists. However, only 20% of multiorgan donors have lungs suitable for transplantation which is far from being sufficient to satisfy the demands for this life-saving procedure.1
It is well recognized that the donor brain death is a major risk factor for decreasing the quality of available organs and for poor outcome following transplantation.2,3 Rapid changes in body hemodynamics, temperature, and hormone balance, along with severe systemic inflammation result in the loss of potential donor tissues and organs. Again, lungs are among the first targets of brain death with pulmonary edema and acute inflammatory injury leading to an irreversible decline in lung function. The mechanisms of this process are well studied and include endothelial cell activation, increased capillary permeability, generation of reactive oxygen species, upregulation of chemokines adhesion molecule, and proinflammatory cytokines leading to leukocyte recruitment and activation.1,4 Parallel endocrinal changes following brain death prompted experimental and clinical studies investigating relationships between hormones and acute tissue injury and the possibility of manipulating hormonal levels to preserve organ integrity and function.
To this end, the study by Ricardo-da-Silva published in the current issue used a rat model of brain death.5 The report continues previous work by this group that described more prominent effects of brain death on lung injury in female donors compared with male donors consistent with clinical observations on the impact of gender in lung transplantation.6,7 In the current study, the authors report rapid changes in the serum estradiol levels following induction of brain death in female rats. Most importantly, supplementing female brain-dead donors with 17β-estradiol ameliorates lung inflammation as evidenced by the decreased levels of proinflammatory cytokines, chemokines, and adhesion molecules, and by reduced cell infiltration, edema and hemorrhage within the lung. These promising observations raise a number of follow-up mechanistic questions that warrant further in vitro experiments and more complex in vivo model systems. In particular, as estrogen can influence a variety of hematopoietic and nonhematopoietic cells,8,9 the precise cell targets of 17β-estradiol in this particular model remain to be determined. The effects of treatment on lung endothelial cells, alveolar macrophages, and infiltrating leukocytes in this particular system must be evaluated to assess the systemic versus local effects of hormonal treatment. This information may provide clues as to the type of estrogen receptors involved in this response to the treatment. Addressing these questions will continue an interesting line of investigation on the role of sex hormones in regulating tissue inflammation.
From a clinical perspective, it is important that significant anti-inflammatory effects are observed even when 17β-estradiol administration is delayed relative to the onset of brain death giving a critical window of opportunity for therapeutic intervention. Given the increasing use of ex vivo organ perfusion before transplantation, another relevant question is whether hormonal therapy will be beneficial if continued after organ retrieval. Although the study was designed to explore the significance in estradiol drop in brain-dead females, it is still of interest whether anti-inflammatory effects of 17β-estradiol can be extended to male donors. Most importantly, orthotopic lung transplantation experiments are ultimately required to test whether 17β-estradiol pretreatment actually improves the outcome of lung transplants from brain-dead female donors.
With the increasing interest in personalized medicine, considering the impact of gender differences on disease initiation and progression is paramount. To date, the influence of gender and sex hormones has been reported in many rodent models of lung injury and disease including nonallergic and allergic inflammation, chronic obstructive pulmonary disease, and lung fibrosis.10 The study by Ricardo-da-Silva and colleagues extends these studies to the area of organ donation and transplantation. The findings in a rat model strongly suggest that 17β-estradiol supplementation may diminish the deleterious effects of donor brain death. Future preclinical and clinical studies will tell whether this strategy expands the pool of donor lungs suitable for transplantation and improves short-term and long-term lung transplant outcomes.
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5. Ricardo-da-Silva FY, Armstrong-Jr R, Vidal-dos-Santos M. 17β-estradiol treatment protects lungs against brain death effects in female rat donor. Transplantation. [Epub ahead of print. October 7, 2020]. doi: 10.1097/TP.0000000000003467
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