HE ACUTE RESPIRATORY DIStress syndrome (ARDS) is a serious form of acute lung injury and has a mortality rate of at least 30%. 1,2 Although the most obvious clinical abnormalities are referable to the lung, the most common cause of death is dysfunction of other organs, termed multiple organ dysfunction syndrome (MODS). [1][2][3] Multiple organ dysfunction syndrome is often irreversible, with mortality ranging from 60% to 98%. [4][5][6] To date, there is neither an effective treatment for MODS nor an effective means for preventing its onset.Mechanical ventilation is essential for patients with ARDS. However, animal and clinical studies have shown that mechanical ventilation can worsen preexisting lung injury and produce ventilator-induced lung injury (VILI). The spectrum of VILI includes not only air leaks and increases in endothelial and epithelial permeability, but also includes increases in pulmonary and systemic inflammatory mediators. [7][8][9] The importance of VILI has recently been highlighted by clinical trials demonstrating that protective ventilatory strategies were associated with decreased serum cytokine and chemokine levels, 10,11 decreased levels of organ dysfunction, 11,12 and decreased mortality in patients with Author Affiliations are listed at the end of this article.

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Ischemia-reperfusion injury is associated with cell death in many organ systems. The role of programmed cell death (PCD) pathways and the ultimate clinical relevance of PCD in the context of lung transplantation (LTx) are unknown.In randomized and blinded studies, rat single LTx was performed in the presence of caspase inhibitors after 'short' (6 h) and 'long' (18 h) periods of cold ischemic storage. Lung function, electron microscopic morphology, caspase 3, 8 and 9 activities and TUNEL assays were evaluated.Endothelial cells and lymphocytes were observed undergoing apoptotic cell death with electron microscopy. Caspase activities were significantly upregulated immediately after the initial flush and increased further during short periods of cold ischemic storage. A significant amount of apoptotic cell death was observed after LTx and reperfusion. Caspase inhibition virtually eliminated apoptotic cell death and led to improved lung function after LTx and reperfusion.Activation of caspases during cold ischemia contributes significantly to cell death in LTx. Suppression of caspase activity appears to decrease apoptosis and improve lung function. Clearly, this needs to be investigated further with more experiments to validate the potential role of caspase inhibition as a therapeutic modality in ischemia-reperfusion-induced lung injury.

Congenital surfactant deficiency (CSD) is a newly identified neonatal lung disorder associated with a variety of molecular defects affecting surfactant synthesis and secretion in alveolar type II cells. The authors present ultrastructural findings of abnormal lamellar bodies in lung biopsies from 4 infants with CSD. All were term infants presenting shortly after birth with severe respiratory failure that was unresponsive to conventional therapy and all died within the first month of life. Lung biopsies were performed between 8 and 25 days of age. Biochemical and molecular studies in 2 unrelated male infants identified SP-B deficiency, one case with 121 ins 2 mutation and the second with a 209 + 4 A > G mutation. Light microscopy in both cases showed features of alveolar proteinosis. Ultrastructurally, alveolar type II cells lacked mature lamellar bodies, and their cytoplasm contained numerous pleomorphic inclusions with membranous and vesicular structures not seen in normal type II cells. The other 2 infants were a pair of siblings in whom molecular studies identified mutations in ABCA3 transporter gene. Light microscopy showed features of acinar dysplasia and desquamative interstitial pneumonitis. TEM studies revealed absence of mature lamellar bodies in type II cells and instead showed a mixture of cytoplasmic electron-dense inclusions with concentric membranes and distinctive electron dense aggregates. The ultrastructural changes in alveolar type II cells correlated well with specific gene defect. In SP-B deficiency, the absence of mature lamellar bodies is consistent with the postulated role for this protein in the formation of lamellar bodies. The lack of mature lamellar bodies in the ABCA3 gene mutations is due to the dysfunction of this endogenous lipid transporter that targets surfactant lipid moieties to the lamellar bodies. The findings demonstrate the importance of TEM studies of lung biopsies from infants with CSD as it is a critical adjunct in the diagnosis of neonatal lung disease and in defining the underlying cellular defects.