Use of high-dose corticosteroids and high-frequency oscillatory ventilation for treatment of a child with diffuse alveolar hemorrhage after bone marrow transplantation: case report and review of the literature.

BACKGROUND: Other than relapse, pulmonary complications are the most common cause of mortality in patients who undergo bone marrow transplantation (BMT). Diffuse alveolar hemorrhage (DAH) is one noninfectious pulmonary complication of BMT. Presenting clinical findings include nonproductive cough usually without hemoptysis, dyspnea, hypoxemia, a decrease in hematocrit, and diffuse infiltrates on chest radiograph. PATIENT: We report a case of DAH after allogeneic BMT in a 6-yr-old female patient. Although a chest radiograph revealed patchy bilateral alveolar densities and large volumes of bright red blood were suctioned from the endotracheal tube, there was no evidence of coagulopathy and no infectious agent was identified on examination of bronchoalveolar lavage fluid, blood, and urine. INTERVENTION: The child was treated with high-dose corticosteroids and high-frequency oscillatory ventilation and experienced a complete clinical recovery from her pulmonary disease. RESULTS: The definition, presenting symptoms, findings and timing, and associated risk factors of DAH after BMT are reviewed. Prospective hypotheses for the pathogenesis of DAH after BMT are presented. Evidence for the role of high-dose corticosteroids for treatment of DAH after BMT and the role of high-frequency oscillatory ventilation for treatment of acute hypoxemic respiratory failure in children with diffuse alveolar disease is also reviewed. CONCLUSION: This case supports the contention that early treatment with high-dose corticosteroids is warranted in children with DAH after BMT.

Exposure to hyperoxia decreases the expression of vascular endothelial growth factor and its receptors in adult rat lungs.

Exposure to high levels of inspired oxygen leads to respiratory failure and death in many animal models. Endothelial cell death is an early finding, before the onset of respiratory failure. Vascular endothelial growth factor (VEGF) is highly expressed in the lungs of adult animals. In the present study, adult Sprague-Dawley rats were exposed to >95% FiO2 for 24 or 48 hours. Northern blot analysis revealed a marked reduction in VEGF mRNA abundance by 24 hours, which decreased to less than 50% of control by 48 hours. In situ hybridization revealed that VEGF was highly expressed in distal airway epithelial cells in controls but disappeared in the oxygen-exposed animals. Immunohistochemistry and Western blot analyses demonstrated that VEGF protein was decreased at 48 hours. TUNEL staining demonstrated the presence of apoptotic cells coincident with the decline in VEGF. Abundance of VEGF receptor mRNAs (Flt-1 and KDR/Flk) decreased in the late time points of the study (48 hours), possibly secondary to the loss of endothelial cells. We speculate that VEGF functions as a survival factor in the normal adult rat lung, and its loss during hyperoxia contributes to the pathophysiology of oxygen-induced lung damage.

Vascular endothelial growth factor is expressed in ovine pulmonary vascular smooth muscle cells in vitro and regulated by hypoxia and dexamethasone.

Chronic lung disease in neonates results from both lung injury and inadequate repair processes. Little is known about the growth factors involved in lung injury and repair, but vascular endothelial growth factor (VEGF) has recently been reported in several animal models of lung injury. VEGF is an endothelial cell-specific mitogen, which is also known as vascular permeability factor because of its ability to induce vascular leak in some tissues. Chronic lung disease is complicated by increased vascular permeability, which can be improved by avoidance of hypoxia and in some cases by dexamethasone therapy. In many cells, hypoxia stimulates VEGF expression. Also, in some cases, dexamethasone blocks VEGF expression. This study examined the role of hypoxia and dexamethasone in regulating the expression of VEGF in pulmonary artery smooth muscle cells. An ovine VEGF cDNA fragment (453 bp) was cloned and found to be highly homologous to known human sequences for VEGF165. Sheep pulmonary artery smooth muscle cells were cultured and exposed to room air, hypoxia, and dexamethasone, alone or in combination for 6 h. At baseline these cells expressed VEGF mRNA at approximately 3.9 kb. The half-life of VEGF mRNA in the smooth muscle cells was 171 min, more than 3-fold longer than previous reports for epithelial cells. Exposure to hypoxia caused a 3-fold increase in mRNA abundance, primarily through transcriptional up-regulation. Dexamethasone blocked the hypoxia-induced increase in VEGF mRNA. The results demonstrate that hypoxia and dexamethasone are regulators of VEGF expression in ovine pulmonary artery smooth muscle cells. It is not known whether VEGF derived from these cells is involved in lung injury and/or normal homeostatsis.