Zonulin is a
protein involved in the regulation of tight junctions (TJ) in epithelial or endothelial cells.
Zonulin is known to affect TJ in gut epithelial cells, but little is known about its influences in other organs. Prehaptoglobin2 has been identified as
zonulin and is related to
serine proteases (
MASPs, C1qrs) that activate the
complement system. The current study focused on the role of
zonulin in development of
acute lung injury (ALI) in C57BL/6 male mice following intrapulmonary deposition of
IgG immune complexes. A
zonulin antagonist (AT-1001) and a related
peptide with permeability agonist activities (AT-1002) were employed and given intratracheally or intravenously. Also,
zonulin was blocked in lung with a
neutralizing antibody. In a dose-dependent manner,
AT-1001 or
zonulin neutralizing antibody attenuated the intensity of ALI (as quantitated by
albumin leak, neutrophil accumulation, and proinflammatory
cytokines). A similar pattern was found using the bacterial
lipopolysaccharide model of ALI. Using confocal microscopy on sections of injured lungs, staining patterns for TJ
proteins were discontinuous, reduced, and fragmented. As expected, the leak of blood products into the alveolar space confirmed the passage of 3 and 20 kDa
dextran, and
albumin. In contrast to
AT-1001, application of the
zonulin agonist AT-1002 intensified ALI.
Zonulin both in vitro and in vivo induced generation of
complement C3a and C5a. Collectively, these data suggest that
zonulin facilitates development of ALI both by enhancing
albumin leak and complement activation as well as increased buildup of neutrophils and
cytokines during development of ALI.