Endostatin levels in ALI BALF reflected the degree of neutrophilia and the extent Brefeldin A structure of the loss of protein selectivity of the alveolar-capillary barrier. Plasma levels of endostatin at the onset of ALI were associated with the severity of physiological derangement. Western blotting confirmed elevated type XVIII collagen precursor levels and multiple amino- and carboxy-terminal fragments in plasma and BALF. Increases in endostatin occur early after OLV and LPS challenge in human volunteers but this is compartmentalised to the lung.Endostatin was detectable in the plasma of all normal subjects studied suggesting a physiological role in the homeostasis of angiogenesis. Elevated endostatin levels have previously been reported in the plasma of patients with preeclampsia, a condition associated with pan-endothelial damage [16].

Similarly, in this study, median plasma level of endostatin in ALI patients were elevated in comparison to both those at risk and normal controls. Plasma levels of endostatin correlated with the severity of the systemic physiological insult rather than lung injury per se. The observed relationship between BALF endostatin and protein permeability index, and the apparent plasma endostatin: ELF endostatin gradient in most of our patients further suggest that alveolar levels of endostatin are raised at least in part because of leakage from the microvasculature into the alveolus at sites of inflammation of the alveolar-capillary membrane. However, in some patients, calculated ELF levels were higher than plasma supporting a role for alveolar generation of endostatin from the type XVIII collagen precursors that we have shown are present.

Endostatin was also elevated in the BALF but not plasma of patients with sepsis who were at risk of ALI. In order to study the time course of changes in endostatin, we evaluated changes in response to two injurious stimuli: OLV and LPS challenge. Both these stimuli induce BAL neutrophilia and increased the PPI in the volunteers/patients. Endostatin was elevated in the BALF but not plasma of the patients after an average of 2.5 hours of OLV and after six hours in the LPS-challenged patients. Thus, endostatin release appears to be compartmentalised to the lung early after such localised injurious stimuli.

The relationships of BALF endostatin with PPI in these in vivo models of the early response to ALI and in established ALI suggest that endostatin generation might be useful as a measure of alveolar capillary damage and support a potential pathophysiological Batimastat role.Endostatin is derived from collagen XVIII which is a major proteoglycan of both endothelial and epithelial basement membrane zones. Specialised capillaries, such as lung alveoli, express type XVIII collagen in their basement membranes. Three forms of collagen XVIII precursor, designated the SHORT, the MIDDLE and the LONG/frizzled variants, are differentially expressed in normal human tissues.