Chemo- and radiotherapy are extensively used to treat various hematological malignancies and solid tumors. Neutropenia and related infection are the most important dose limiting toxicities of these anti-cancer treatments, impacting on quality of life and clinical outcomes, with the potential to cause death. Neutropenia- related pneumonias are involved in 40% infection at a site other than blood alone, and usually treated with broad-spectrum antibiotic therapy and granulocyte colony-stimulating factor (G-CSF) therapy. However, not all patients respond to antibiotic treatment and G-CSF therapy is often associated with side-effects such as bone pain, headache, fatigue, nausea, and higher risk of getting leukemia. The long-term goal of this project is to explore another strategy for treating/preventing neutropenia-related pneumonia - via enhancing neutrophil functions (e.g. recruitment, survival, and bacteria killing) in neutropenic patients. We will try to achieve this by elevating intracellular PtdIns(3,4,5)P3 signaling pathway which has been implicated in a variety of neutrophil functions. Recently, we have shown that the responsiveness of neutrophil to chemoattractant stimulation is much enhanced in PTEN knockout mice in which the PtdIns(3,4,5)P3 signaling is hyperactivated. The recruitment of neutrophils to the inflamed peritoneal cavity was significantly enhanced in these mice. In addition, augmenting PtdIns(3,4,5)P3 signal via depleting PTEN prevents neutrophil spontaneous death. Our preliminary data also demonstrated that the PTEN null neutrophils possess an enhanced bacteria killing capability and their recruitment to the inflamed lungs was also augmented. Based on these intriguing results, we hypothesize that augmentation of PtdIns(3,4,5)P3 signaling pathway should be a legitimate therapeutic strategy for the treatment of neutropenia-related pneumonia. In this proposed research, we will directly examine whether disruption of PTEN can augment neutrophil recruitment and survival in neutropenia-related pneumonia (Aim I), enhance neutrophil bacterial killing capability, and alleviate the severity of neutropenia- related pneumonia (Aim II). In addition, since alveolar macrophages also play a critical rolein host defense against respiratory tract infections, whether disruption of PTEN can also enhance the function of alveolar macrophages will be investigated (Aim III). Lastly, PtdIns(3,4,5)P3 signaling can also be augmented by disrupting InsP3KB;and thus we will explore whether disruption of InsP3KB can also reduce the severity of neutropenia-related pneumonia (Aim IV).

Public Health Relevance

Experiments proposed in this study will provide insight into the mechanism of action of PtdIns(3,4,5)P3 pathway in elevating neutrophil and macrophage function in lung infection and inflammation, with the ultimate goal of solidifying PtdIns(3,4,5)P3-related pathways as novel therapeutic targets for treatment of neutropenia- related pneumonia. This will be an important and necessary complementation to the current antibiotic and G- CSF therapies. In addition, although we focus on neutropenia-related pneumonia in this application, the same strategy can be readily applied to other neutropenia-related infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092020-04
Application #
8277908
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Harabin, Andrea L
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$430,650
Indirect Cost
$183,150
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Damnernsawad, Alisa; Kong, Guangyao; Wen, Zhi et al. (2016) Kras is Required for Adult Hematopoiesis. Stem Cells 34:1859-71
Li, Zhenzhen; Ye, Zhou; Zhang, Xiaolong et al. (2016) E1A-engineered human umbilical cord mesenchymal stem cells as carriers and amplifiers for adenovirus suppress hepatocarcinoma in mice. Oncotarget 7:51815-51828
Bajrami, Besnik; Zhu, Haiyan; Kwak, Hyun-Jeong et al. (2016) G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling. J Exp Med 213:1999-2018
Kwak, Hyun-Jeong; Liu, Peng; Bajrami, Besnik et al. (2015) Myeloid cell-derived reactive oxygen species externally regulate the proliferation of myeloid progenitors in emergency granulopoiesis. Immunity 42:159-71
Luo, Hongbo R; Mondal, Subhanjan (2015) Molecular control of PtdIns(3,4,5)P3 signaling in neutrophils. EMBO Rep 16:149-63
Kaunisto, Aura; Henry, Whitney S; Montaser-Kouhsari, Laleh et al. (2015) NFAT1 promotes intratumoral neutrophil infiltration by regulating IL8 expression in breast cancer. Mol Oncol 9:1140-54
Loison, Fabien; Zhu, Haiyan; Karatepe, Kutay et al. (2014) Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation. J Clin Invest 124:4445-58
Zhao, Fan; Li, Jingyu; Zhou, Ning et al. (2014) De novo chemoattractants form supramolecular hydrogels for immunomodulating neutrophils in vivo. Bioconjug Chem 25:2116-22
Loison, Fabien; Xu, Yuanfu; Luo, Hongbo R (2014) Proteinase 3 and Serpin B1: a novel pathway in the regulation of caspase-3 activation, neutrophil spontaneous apoptosis, and inflammation. Inflamm Cell Signal 1:
Luo, Hongbo R (2014) A dual regulator of neutrophil recruitment. Blood 123:1983-5

Showing the most recent 10 out of 23 publications