Background: Our previous work demonstrated that the extracellular matrix protein
mindin contributes to allergic airways disease. However, the role of mindin in
nonallergic airways disease has not previously been explored.Objectives: We hypothesized that mindin would contribute to airways disease after
inhalation of either lipopolysaccharide (LPS) or ozone.Methods: We exposed C57BL/6J and mindin-deficient (–/–)
mice to aerosolized LPS (0.9 μg/m3 for 2.5 hr), saline, ozone
(1 ppm for 3 hr), or filtered air (FA). All mice were evaluated 4 hr after
LPS/saline
exposure or 24 hr after ozone/FA exposure. We characterized
the physiological and biological responses by analysis of airway
hyperresponsiveness (AHR) with a computer-controlled small-animal ventilator
(FlexiVent), inflammatory cellular recruitment, total protein in bronchoalveolar
lavage fluid (BALF), proinflammatory cytokine profiling, and ex
vivo bronchial ring studies.Results: After inhalation of LPS, mindin–/– mice
demonstrated significantly reduced total cell and neutrophil recruitment into
the airspace compared with their wild-type counterparts.
Mindin–/– mice also exhibited reduced
proinflammatory cytokine production and lower AHR to methacholine challenge by
FlexiVent. After inhalation of ozone, mice had no detectible differences in
cellular inflammation or total BALF protein dependent on mindin. However,
mindin–/– mice were protected from increased
proinflammatory cytokine production and AHR compared with their C57BL/6J
counterparts. After ozone exposure, bronchial rings derived from
mindin–/– mice demonstrated reduced constriction in
response to carbachol.Conclusions: These data demonstrate that the extracellular matrix protein mindin
modifies the airway response to both LPS and ozone. Our data support a conserved
role of mindin in production of proinflammatory cytokines and the development of
AHR in two divergent models of reactive airways disease, as well as a role of
mindin in airway smooth muscle contractility after exposure to ozone.