RESUMO
INTRODUCTION: Influenza infects millions of people each year causing respiratory distress and death in severe cases. On average, 200,000 people annually are hospitalized in the United States for influenza related complications. Tissue inhibitor of metalloproteinase-1 (TIMP-1), a secreted protein that inhibits MMPs, has been found to be involved in lung inflammation. Here, we evaluated the role of TIMP-1 in the host response to influenza-induced lung injury. METHODS: Wild-type (WT) and Timp1-deficient (Timp1-/-) mice that were 8-12 weeks old were administered A/PR/8/34 (PR8), a murine adapted H1N1 influenza virus, and euthanized 6 days after influenza installation. Bronchoalveolar lavage fluid and lungs were harvested from each mouse for ELISA, protein assay, PCR, and histological analysis. Cytospins were executed on bronchoalveolar lavage fluid to identify immune cells based on morphology and cell count. RESULTS: WT mice experienced significantly more weight loss compared to Timp1-/- mice after influenza infection. WT mice demonstrated more immune cell infiltrate and airway inflammation. Interestingly, PR8 levels were identical between the WT and Timp1-/- mice 6 days post-influenza infection. CONCLUSION: The data suggest that Timp1 promotes the immune response in the lungs after influenza infection facilitating an injurious phenotype as a result of influenza infection.
Assuntos
Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Hemorragia/virologia , Vírus da Influenza A Subtipo H1N1 , Infecções por Orthomyxoviridae/complicações , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/virologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Contagem de Eritrócitos , Eritrócitos , Hemorragia/genética , Contagem de Leucócitos , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos , Infecções por Orthomyxoviridae/virologia , Carga Viral/genética , Redução de Peso/genéticaRESUMO
High-grade serous ovarian cancers (HGSOC) are genomically complex, heterogeneous cancers with a high mortality rate, due to acquired chemoresistance and lack of targeted therapy options. Cyclin-dependent kinase inhibitors (CDKi) target the retinoblastoma (RB) signaling network, and have been successfully incorporated into treatment regimens for breast and other cancers. Here, we have compared mechanisms of response and resistance to three CDKi that target either CDK4/6 or CDK2 and abrogate E2F target gene expression. We identify CCNE1 gain and RB1 loss as mechanisms of resistance to CDK4/6 inhibition, whereas receptor tyrosine kinase (RTK) and RAS signaling is associated with CDK2 inhibitor resistance. Mechanistically, we show that ETS factors are mediators of RTK/RAS signaling that cooperate with E2F in cell cycle progression. Consequently, CDK2 inhibition sensitizes cyclin E1-driven but not RAS-driven ovarian cancer cells to platinum-based chemotherapy. In summary, this study outlines a rational approach for incorporating CDKi into treatment regimens for HGSOC.
