BackgroundResistin-like molecule alpha or found in inflammatory zone protein (Fizz1) is increased in pulmonary epithelial cells and also in limited amounts by other lung cells during various lung injuries and fibrosis. However, the direct role of Fizz1 produced in the pulmonary epithelium has not been determined.MethodsFizz1 Transgenic mice (CCSP/Fizz1) were generated that overexpress Fizz1 in the lung epithelium under the control of a doxycycline (Dox) inducible lung epithelial cell specific promoter Scgb1a1 (Clara cell secretory protein, CCSP). Histology and FACS analysis of lung cells were used to identify the direct effects of Fizz1 in the transgenic mice (Dox treated) when compared with control (CCSP/-) mice. Intratracheal bleomycin sulfate or silica in saline and saline alone were used to study the role of Fizz1 during bleomycin- and silica-induced pulmonary fibrosis in CCSP/Fizz1 and CCSP/- mice. Weight change, pulmonary inflammation, and fibrosis were assessed 10 days post bleomycin or 28 days post silica challenge.ResultsWhen CCSP/Fizz1 mice were fed Dox food, elevated Fizz1 protein was detected in lung homogenates by western blot. Lungs of mice in which Fizz1 was induced in the epithelium contained increased lung cells staining for CD11c and F4/80 by FACS analysis consistent with increased dendritic cells however, no changes were observed in the percentage of interstitial macrophages compared to CCSP/- controls. No significant changes were found in the lung histology of CCSP/Fizz1 mice after up to 8 weeks of overexpression compared to CCSP/- controls. Overexpression of Fizz1 prior to challenge or following challenge with bleomycin or silica did not significantly alter airway inflammation or fibrosis compared to control mice.ConclusionsThe current study demonstrates that epithelial cell derived Fizz1 is sufficient to increase the bone-marrow derived dendritic cells in the lungs, but it is not sufficient to cause lung fibrosis or alter chemical or particle-induced fibrosis.

C3H/HeJ mice develop an increase in terminal air space area detectable by postnatal d 14 that persists into adulthood compared with strain-matched controls (C3H/SnJ, C3H/OuJ). Morphometric quantification revealed a 50% increase in terminal air space area by postnatal d 14 and a 2.3-fold increase by 2 mo of age in C3H/HeJ mice. Bacteriologic cultures obtained from the left lung on postnatal d 7 revealed Ͼ100 colony-forming units (CFU)/left lung of predominantly Gram-negative bacteria (GNB) (Escherichia coli and Proteus mirabilis) in 13 of the 14 C3H/HeJ mice compared with 0 of 12 controls demonstrating colonization of the developing lung in C3H/HeJ mice. An approximately threefold increase in macrophages from bronchoalveolar lavage, threefold increases in matrix metalloproteinase 12 (MMP-12) mRNA and protein levels and elevated levels of proinflammatory cytokines monocyte chemoattractant protein (MCP-1) and keratinocyte-derived cytokine (KC) were also found. B ronchopulmonary dysplasia (BPD) is an important cause of morbidity and mortality in preterm infants, affecting 40% of all infants born with a birth weight Ͻ1000 g (1). The routine use of antenatal steroids, surfactant, and gentler ventilation strategies has led to the emergence of the "new" BPD, which predominantly affects extremely low birth weight infants (2,3) who despite requiring minimal or no ventilatory support still progress to BPD (3,4). Lung pathology in these infants reveals large, simplified alveolar structures and abnormalities in microvasculature development with variable interstitial cellularity (5). Although BPD is a multifaceted disease, lung infections have been implicated in the pathogenesis of BPD (6,7). Ureaplasma urealyticum, Gram-positive bacteria, and GNB frequently colonize lungs of the premature infant and have been associated with BPD (6 -9). The underlying mechanisms by which bacterial colonization of the immature lung can result in morphologic changes seen in BPD have not been elucidated.Mice are born with lungs in the saccular phase of development; alveolarization is initiated around postnatal d 5 and is completed in the first 2-3 wk of life (10). Because lung development in mice parallels that in preterm infants who are born with their lungs in late canalicular or early saccular phase (11), mice can serve as a model of the developing premature human lung. It is well established that the preterm infant is at increased risk of infections because various components of the immune system are not well developed (12,13). Decreased expression of innate host defense molecules might alter susceptibility to bacterial colonization and chronic inflammation leading to morphologic changes in the lung architecture characteristic of BPD.Mammalian Toll-like receptors are pattern recognition receptors (PRRs) that interact with pathogen-associated molecular patterns and serve as the recognition and effector arm of the innate immune response (14,15). Toll-like receptor 4 (TLR4) serves as a PRR for GNB by recognizing lipopolysaccharide (L...