Enhanced early vascular permeability in gelatinase B (MMP-9)-deficient mice: putative contribution of COX-1-derived PGE2 of macrophage origin

Abstract

Increased vascular permeability leading to vascular leakage is a central feature of all inflammatory reactions and is critical for the formation of an inflammatory exudate. The leakage occurs because of gap formation between endothelial cells and breakdown of the basement membrane barriers. The present study aimed to investigate the role of gelatinase B [matrix metalloproteinase 9 (MMP-9)], known to be involved in neutrophil exudation, in changes of vascular permeability at the early stages of acute zymosan peritonitis. We show that although MMP-9 is being released already within the first minutes of peritonitis, its lack, induced pharmacologically or genetically, does not decrease but rather increases vasopermeability. In mice treated with an inhibitor of gelatinases (A and B), a tendency to increased vasopermeability existed, and in MMP-9-/- mice [knockout (KO)], the difference was statistically significant in comparison with their controls. Moreover, in intact KO mice, significantly augmented production of prostaglandin E(2) (PGE(2)) of cyclooxygenase 1 (COX-1) origin was detected, and depletion of peritoneal macrophages, but not mast cells, decreased vasopermeability in KO mice. Thus, the increase of vasopermeability observed on KO mice is a result of the increased production of COX-1-derived PGE(2) by peritoneal macrophages. We conclude that genetic deficiency in gelatinase B might lead to the development of a compensatory mechanism involving the COX pathway.

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury

“…Vascular injury during mechanical ventilation is another mechanism of VILI, so the role of MMP-9 in the maintenance of the vascular wall should be taken into account. Moreover, it has been reported that these knockout mice have an increased vascular permeability after inflammation, which is mediated by prostaglandins (26). However, lack of differences in lung edema (wet-to-dry weight, protein concentration in BAL) between genotypes suggest that the protective effects are more related to the modulation of the inflammatory response than to a direct effect on vascular permeability.…”

Role of lymphocytes in the course of murine zymosan-induced peritonitis

“…Since then many aspects of this inflammation have been described in detail elsewhere [2][3][4][5][6][7][8][9][10][11][12] confirming the utility of this model. Moreover, murine zymosan peritonitis models the peritoneal inflammation that often accompanies peritoneal dialyses and ulcer perforations, and its value (as such a model) is further enhanced by the (still) high morbidity rates in human peritonitis [13].…”

“…Thirty minutes later the animals were killed and their peritoneal cavities were lavaged with 1.5 ml of saline as described above. The lavage fluid was centrifuged and the absorbance of dye in the supernatant was measured at 620 nm with a Microplate Reader Expert Plus (ASYS Hitech) as described previously [5,8].…”

“…Zymography was performed as described [4,5]. Briefly, samples of peritoneal exudate were normalized for protein concentration.…”

Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Prostaglandin E 2 Production through Cyclooxygenase 1, Which Is Dependent on the ERK1/2-p-C/EBP-β Pathway

“…For example, COX-1 was found to promote PGE 2 production and control the thermoregulatory response to influenza A virus infection at 4 dpi in mice (38). Mice deficient in gelatinase B (matrix metallopeptidase 9 [MMP-9]) develop a compensatory mechanism involving the COX-1-PGE 2 pathway in macrophages, resulting in enhanced early vascular permeability (39). Mounting evidence has shown that the pattern of expression of the two COX isoforms is far more complex than the general concept of constitutive (COX-1) and inducible (COX-2) expression (37,40).…”