Lack of matrix metalloproteinase 3 in mouse models of lung injury ameliorates the pulmonary inflammatory response in female but not in male mice.
The acute respiratory distress syndrome (ARDS) is a complex pulmonary disorder in which the local release of cytokines and chemokines appears central to the pathophysiology.



Based on the known role of matrix metalloproteinase-3 (MMP3) in inflammatory processes, the objective was to examine the role of MMP3 in the pathogenesis of ARDS through the modulation of pulmonary inflammation.



Female and male, wild type (MMP3+/+) and knock out (MMP3-/-) mice were exposed to two, clinically relevant models of ARDS including (i) lipopolysaccharide (LPS)-induced lung injury, and (ii) hydrochloric acid-induced lung injury. Parameters of lung injury and inflammation were assessed through measurements in lung lavage including total protein content, inflammatory cell influx, and concentrations of mediators such as TNF-α, IL-6, G-CSF, CXCL1, CXCL2, and CCL2. Lung histology and compliance were also evaluated in the LPS model of injury.



Following intra-tracheal LPS instillation, all mice developed lung injury, as measured by an increase in lavage neutrophils, and decrease in lung compliance, with no overall effect of genotype observed. Increased concentrations of lavage inflammatory cytokines and chemokines were also observed following LPS injury, however, LPS-instilled female MMP3-/-mice had lower levels of inflammatory mediators compared to LPS-instilled female MMP3+/+mice. This effect of the genotype was not observed in male mice. Similar findings, including the MMP3-related sex differences, were also observed after acid-induced lung injury.



MMP3 contributes to the pathogenesis of ARDS, by affecting the pulmonary inflammatory response in female mice in relevant models of lung injury.
a Department of Physiology and Pharmacology , Lawson Health Research Institute, Western University , London , Ontario , Canada.
Valeria
V
Puntorieri
a Department of Physiology and Pharmacology , Lawson Health Research Institute, Western University , London , Ontario , Canada.
Lynda A
LA
McCaig
b Department of Pathology and Laboratory Medicine , Western University , London , Ontario , Canada.
Christopher J
CJ
Howlett
c Department of Medicine , Western University , London , Ontario , Canada.
Li-Juan
LJ
Yao
c Department of Medicine , Western University , London , Ontario , Canada.
James F
JF
Lewis
a Department of Physiology and Pharmacology , Lawson Health Research Institute, Western University , London , Ontario , Canada.|c Department of Medicine , Western University , London , Ontario , Canada.
Cory M
CM
Yamashita
a Department of Physiology and Pharmacology , Lawson Health Research Institute, Western University , London , Ontario , Canada.|c Department of Medicine , Western University , London , Ontario , Canada.
Ruud A W
RA
Veldhuizen
D055371:Acute Lung Injury / Q000139:chemically induced; D000818:Animals; D005260:Female; D006801:Humans; D006851:Hydrochloric Acid / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D011014:Pneumonia / Q000139:chemically induced*; D012128:Respiratory Distress Syndrome / Q000209:etiology*; D012737:Sex Factors
D008070:Lipopolysaccharides; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D006851:Hydrochloric Acid
acute respiratory distress syndrome; lung injury; matrix metalloproteinases; pulmonary inflammation