c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice.

RATIONALE: Previously, we demonstrated a candidate region for susceptibility to airspace enlargement on mouse chromosome 5. However, the specific candidate genes within this region accounting for emphysema-like changes remain unrecognized. c-Kit is a receptor tyrosine kinase within this candidate gene region that has previously been recognized to contribute to the survival, proliferation, and differentiation of hematopoietic stem cells. Increases in the percentage of cells expressing c-Kit have previously been associated with protection against injury-induced emphysema. OBJECTIVES: Determine whether genetic variants of c-Kit are associated with spontaneous airspace enlargement. METHODS: Perform single-nucleotide polymorphism association studies in the mouse strains at the extremes of airspace enlargement phenotype for variants in c-Kit tyrosine kinase. Characterize mice bearing functional variants of c-Kit compared with wild-type controls for the development of spontaneous airspace enlargement. Epithelial cell proliferation was measured in culture. MEASUREMENTS AND MAIN RESULTS: Upstream regulatory single-nucleotide polymorphisms in the divergent mouse strains were associated with the lung compliance difference observed between the extreme strains. c-Kit mutant mice (Kit(W-sh)/(W-sh)), when compared with genetic controls, developed altered lung histology, increased total lung capacity, increased residual volume, and increased lung compliance that persist into adulthood. c-Kit inhibition with imatinib attenuated in vitro proliferation of cells expressing epithelial cell adhesion molecule. CONCLUSIONS: Our findings indicate that c-Kit sustains and/or maintains normal alveolar architecture in the lungs of mice. In vitro data suggest that c-Kit can regulate epithelial cell clonal expansion. The precise mechanisms that c-Kit contributes to the development of airspace enlargement and increased lung compliance remain unclear and warrants further investigation.

TLR4 is necessary for hyaluronan-mediated airway hyperresponsiveness after ozone inhalation.

RATIONALE: Ozone is a common environmental air pollutant that contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced airway hyperresponsiveness, remain poorly understood. We have previously reported that toll-like receptor 4 (TLR4)-deficient animals are protected against ozone-induced airway hyperresponsiveness (AHR) and that hyaluronan (HA) mediates ozone-induced AHR. However, the relation between TLR4 and hyaluronan in the airway response to ozone remains unexplored. OBJECTIVES: We hypothesized that HA acts as an endogenous TLR4 ligand for the development of AHR after ozone-induced environmental airway injury. METHODS: TLR4-deficient and wild-type C57BL/6 mice were exposed to either inhaled ozone or intratracheal HA and the inflammatory and AHR response was measured. MEASUREMENTS AND MAIN RESULTS: TLR4-deficient mice have similar levels of cellular inflammation, lung injury, and soluble HA levels as those of C57BL/6 mice after inhaled ozone exposure. However, TLR4-deficient mice are partially protected from AHR after ozone exposure as well as after direct intratracheal instillation of endotoxin-free low molecular weight HA. Similar patterns of TLR4-dependent cytokines were observed in the bronchial alveolar lavage fluid after exposure to either ozone or HA. Exposure to ozone increased immunohistological staining of TLR4 on lung macrophages. Furthermore, in vitro HA exposure of bone marrow-derived macrophages induced NF-kappaB and production of a similar pattern of proinflammatory cytokines in a manner dependent on TLR4. CONCLUSIONS: Our observations support the observation that extracellular matrix HA contributes to ozone-induced airways disease. Furthermore, our results support that TLR4 contributes to the biological response to HA by mediating both the production of proinflammatory cytokines and the development of ozone-induced AHR.

RETRACTED: NAD(P)H:quinone oxidoreductase 1 protects lungs from oxidant-induced emphysema in mice.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Authors. Since learning of potential discrepancies between the raw data from the animal pulmonary physiology laboratory at Duke that were used to calculate the in vivo pulmonary mechanics and the re-exported machine-generated raw data, some studies published elsewhere have been replicated successfully. However it is not possible to replicate this study as the NQO1-deficient mice on the C57BL/6 background are no longer available from the NCI. The authors recognize that previous work to identify differences in alveolar size can vary dependent on background strain when comparing inbred mouse strains (Soutiere SE et al Resp Physiol Neurobiol 2004;140(3)183­91 doi: 10.1016/j.resp.2004.02.003). Because of the prolonged period of time required to successfully backcross NQO1-deficient animals onto C57BL/6J background and the time required to repeat studies presented in this manuscript the authors think it does not seem feasible to conduct replicate studies in a reasonable timeline. Therefore, the most appropriate course of action is to retract the report as it is the authors' goal to maintain accuracy of the scientific record to the best of their ability. The authors offer sincere apologies to the scientific community.