RESUMEN
Pneumocystis species are respiratory fungal pathogens that cause life-threatening opportunistic infections in immunocompromised hosts. Pneumocystis typically evade pulmonary innate immunity but are efficiently eradicated by a functional adaptive immune response. FVB/NJ mice are unique in that they display protective alveolar macrophage-dependent innate immunity against Pneumocystis, and remain resistant to infection even in the absence of CD4+ T lymphocyte function. FVB/NJ alveolar macrophages (AMs) were found to display an M2-biased phenotype at baseline, which was potentiated after stimulation with Pneumocystis, suggesting that macrophage polarization may dictate the outcome of the Pneumocystis-macrophage interaction. To determine whether Stat6, a key global regulator of M2 polarization, was required for FVB/NJ innate immunity, FVB Stat6-/- mice were generated. FVB Stat6-deficient AMs were markedly impaired in their ability to polarize to an M2 phenotype when stimulated with Th2 cytokines. However, FVB Stat6-/- mice remained highly resistant to infection, indicating that Stat6 signaling is dispensable for innate FVB/NJ resistance. Despite the loss of Stat6 signaling, primary AMs from FVB Stat6-/- mice maintained baseline expression of M2 markers, and also strongly upregulated M2-associated genes following direct stimulation with Pneumocystis. Additional FVB/NJ knockout strains were generated, but only FVB MerTK-/- mice showed a marginally increased susceptibility to Pneumocystis infection. Together, these findings demonstrate that effective FVB/NJ innate immunity against Pneumocystis does not require Stat6 signaling and suggest that alternative pathways regulate M2 bias and macrophage-mediated innate resistance in FVB/NJ mice.
RESUMEN
Pulmonary fibrosis is a common and dose-limiting side-effect of ionizing radiation used to treat cancers of the thoracic region. Few effective therapies are available for this disease. Pulmonary fibrosis is characterized by an accumulation of myofibroblasts and excess deposition of extracellular matrix proteins. Although prior studies have reported that ionizing radiation induces fibroblast to myofibroblast differentiation and collagen production, the mechanism remains unclear. Transforming growth factor-ß (TGF-ß) is a key profibrotic cytokine that drives myofibroblast differentiation and extracellular matrix production. However, its activation and precise role in radiation-induced fibrosis are poorly understood. Recently, we reported that lactate activates latent TGF-ß through a pH-dependent mechanism. Here, we wanted to test the hypothesis that ionizing radiation leads to excessive lactate production via expression of the enzyme lactate dehydrogenase-A (LDHA) to promote myofibroblast differentiation. We found that LDHA expression is increased in human and animal lung tissue exposed to ionizing radiation. We demonstrate that ionizing radiation induces LDHA, lactate production, and extracellular acidification in primary human lung fibroblasts in a dose-dependent manner. We also demonstrate that genetic and pharmacologic inhibition of LDHA protects against radiation-induced myofibroblast differentiation. Furthermore, LDHA inhibition protects from radiation-induced activation of TGF-ß. We propose a profibrotic feed forward loop, in which radiation induces LDHA expression and lactate production, which can lead to further activation of TGF-ß to drive the fibrotic process. These studies support the concept of LDHA as an important therapeutic target in radiation-induced pulmonary fibrosis.
Asunto(s)
L-Lactato Deshidrogenasa/metabolismo , Miofibroblastos/efectos de la radiación , Animales , Diferenciación Celular/efectos de la radiación , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Gosipol/farmacología , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/antagonistas & inhibidores , Lactato Deshidrogenasa 5 , Ácido Láctico/biosíntesis , Pulmón/enzimología , Pulmón/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Miofibroblastos/citología , Miofibroblastos/enzimología , Fibrosis Pulmonar/enzimología , Fibrosis Pulmonar/etiología , Traumatismos por Radiación/enzimología , Traumatismos por Radiación/etiología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-gamma agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARgamma agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARgamma agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARgamma and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow.
RESUMEN
Three years of field data, classical linear reservoir theory, and a new dissolution model confirm the hypothesis that residual chloride from highway deicing applications dissolves into precipitation throughout the year. The measured input includes 52 storm hyetographs and logs of salt and premix applications on an access road with a closed drainage system subject to runoff, interflow, and baseflow. The output data feature discharge and conductivity in an outlet weir measured continuously from February 1998 to May 2000. Individual storm hydrographs and pollutographs yield calibrated first flush dissolved chloride concentrations and residual solid chloride loads that persist at appreciable levels over the entire period of record. The storm calibrations imply a source strength w of 2.01 x 10(-6) s(-1) that accurately models chloride dissolution kinetics through three salt seasons on the access road. This w rests on physically plausible values for the depression storage depth zeta (3 mm) and porosity n (0.40) that store the residual chloride.