Although IL-6 has been implicated in the triggering process of sepsis and correlates with its severity [35], IL-1�� has been associated with the degree of VILI [32]. On the other hand, mRNA expression of PCIII was determined because it is the first collagen to be remodeled in the development/course of lung fibrogenesis [36], as well as being an early marker of lung parenchyma remodeling [32,37]. We also measured the levels of mRNA expression of caspase-3, because it represents a surrogate parameter for the final step of apoptosis [38]. Finally, the effects of volemic status and RM on mRNA expressions of ICAM-1 and VCAM-1 were determined because these adhesion molecules are involved in the accumulation of neutrophils in the lung tissue, playing a crucial role in the pathogenesis of VILI [39].Effects of volemia on lung and distal organ injuryIn severe sepsis aggressive fluid resuscitation is recommended [40]. However, in ALI/ARDS the optimal fluid management protocol is yet to be established. Conservative management of ALI/ARDS prescribes that fluid intake be restricted in an attempt to decrease pulmonary edema, shorten the duration of mechanical ventilation, and improve survival. A possible risk of this approach is a decrease in cardiac output and worsening of distal organ function, both of which are reversed with the liberal approach.Our data show that a hypervolemic status led to increased lung, but not distal organ injury. In fact, hypervolemia was associated with a more pronounced detachment of the alveolar-capillary membrane as well as injury of endothelial cells. On the other hand, fluid restriction did not increase distal organ injury. Different mechanisms could explain the adverse effects of hypervolemia on lung injury: 1) increased hydrostatic pressures; and 2) augmented capillary blood flow and volume.During hypervolemia, increased pulmonary edema was induced by altered permeability of the alveolar capillary membrane, which is a common finding in sepsis [41], combined with higher hydrostatic pressure. In the presence of pulmonary edema, the increase in hydrostatic pressures along the ventral-dorsal gradient promoted a reduction in normally aerated tissue, contributing to increased stress/strain and cyclic collapse/reopening [42].Hypervolemic groups were characterized by impaired oxygenation and higher Est,L. The reduction in oxygenation can be attributed to increased edema and atelectasis. The increase in Est,L suggested higher lung stress in aerated lung areas during inflation. In addition, as the same VT was applied in all groups and hypervolemia decreased the normally aerated tissue, the strain in the hypervolemic group may be increased.