Transgenic Overexpression of Granulocyte Macrophage-Colony Stimulating Factor in the Lung Prevents Hyperoxic Lung Injury

University of California, San Francisco, San Francisco, California, United States
American Journal Of Pathology (Impact Factor: 4.59). 12/2003; 163(6):2397-406. DOI: 10.1016/S0002-9440(10)63594-8
Source: PubMed


Granulocyte macrophage-colony stimulating factor (GM-CSF) plays an important role in pulmonary homeostasis, with effects on both alveolar macrophages and alveolar epithelial cells. We hypothesized that overexpression of GM-CSF in the lung would protect mice from hyperoxic lung injury by limiting alveolar epithelial cell injury. Wild-type C57BL/6 mice and mutant mice in which GM-CSF was overexpressed in the lung under control of the SP-C promoter (SP-C-GM mice) were placed in >95% oxygen. Within 6 days, 100% of the wild-type mice had died, while 70% of the SP-C-GM mice remained alive after 10 days in hyperoxia. Histological assessment of the lungs at day 4 revealed less disruption of the alveolar wall in SP-C-GM mice compared to wild-type mice. The concentration of albumin in bronchoalveolar lavage fluid after 4 days in hyperoxia was significantly lower in SP-C-GM mice than in wild-type mice, indicating preservation of alveolar epithelial barrier properties in the SP-C-GM mice. Alveolar fluid clearance was preserved in SP-C-GM mice in hyperoxia, but decreased significantly in hyperoxia-exposed wild-type mice. Staining of lung tissue for caspase 3 demonstrated increased apoptosis in alveolar wall cells in wild-type mice in hyperoxia compared to mice in room air. In contrast, SP-C-GM mice exposed to hyperoxia demonstrated only modest increase in alveolar wall apoptosis compared to room air. Systemic treatment with GM-CSF (9 micro g/kg/day) during 4 days of hyperoxic exposure resulted in decreased apoptosis in the lungs compared to placebo. In studies using isolated murine type II alveolar epithelial cells, treatment with GM-CSF greatly reduced apoptosis in response to suspension culture. In conclusion, overexpression of GM-CSF enhances survival of mice in hyperoxia; this effect may be explained by preservation of alveolar epithelial barrier function and fluid clearance, at least in part because of reduction in hyperoxia-induced apoptosis of cells in the alveolar wall.

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Available from: Robert Paine, Jun 20, 2014
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    • "These findings illustrate that not only the relative absence, but also the abundance , of GM-CSF can have significant effects on the immune system. Besides exogenous administration of GM-CSF, there have been numerous studies in which GM-CSF was overexpressed endogenously , either transiently using adenoviral vectors (Steinwede et al., 2011; Xing et al., 1996) or constitutively using transgenic mice (Biondo et al., 2001; Breuhahn et al., 2000; Lang et al., 1987; Paine et al., 2003; Van Nieuwenhuijze et al., unpublished observations ). A common feature of these transgenic animal models was local macrophage and DC recruitment/differentiation, with phenotypes including blindness due to accumulation of macrophages in the eye, myelo-proliferation and inflammatory tissue destruction (Lang et al., 1987), the induction of autoimmune gastritis (Biondo et al., 2001), and the development of disseminated histiocytosis (Van Nieuwenhuijze et al., unpublished observations). "
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    ABSTRACT: GM-CSF is a well-known haemopoietic growth factor that is used in the clinic to correct neutropaenia, usually as a result of chemotherapy. GM-CSF also has many pro-inflammatory functions and recent data implicates GM-CSF as a key factor in Th17 driven autoimmune inflammatory conditions. In this review we summarize the findings that have led to the development of GM-CSF antagonists for the treatment of autoimmune diseases like rheumatoid arthritis (RA) and discuss some results of recent clinical trials of these agents.
    Molecular Immunology 08/2013; 56(4):675-682. DOI:10.1016/j.molimm.2013.05.002 · 2.97 Impact Factor
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    • "Notably, our own studies demonstrate that epithelial repair processes were primed already in the pro-inflammatory phase of acute lung injury and elucidate a key role of alveolar macrophage TNF-α inducing AEC repair via induction of autocrine epithelial GM-CSF signaling (Cakarova et al., 2009). In support of these findings, GM-CSF has been recognized as potent growth factor for AEC in vitro and in lung injury models in vivo (Huffman Reed et al., 1997; Paine et al., 2003). Furthermore, we demonstrated proliferative effects of the macrophage cytokine MIF (macrophage migration inhibitory factor) which were mediated by the MIF receptor CD74 expressed on AEC II (Marsh et al., 2009). "
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    ABSTRACT: Lung macrophages are long living cells with broad differentiation potential, which reside in the lung interstitium and alveoli or are organ-recruited upon inflammatory stimuli. A role of resident and recruited macrophages in initiating and maintaining pulmonary inflammation in lung infection or injury has been convincingly demonstrated. More recent reports suggest that lung macrophages are main orchestrators of termination and resolution of inflammation. They are also initiators of parenchymal repair processes that are essential for return to homeostasis with normal gas exchange. In this review we will discuss cellular cross-talk mechanisms and molecular pathways of macrophage plasticity which define their role in inflammation resolution and in initiation of lung barrier repair following lung injury.
    Frontiers in Immunology 11/2011; 2:65. DOI:10.3389/fimmu.2011.00065
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    • "Monocytes recruited into the lung play a critical important role in clearing foreign material such as particles from the lung which underscores the importance of mediators such as GM-CSF as both a pro-inflammatory but also an anti-inflammatory mediator. This anti-inflammatory role is supported by studies that showed that GM-CSF has a protective role against pulmonary fibrosis [24] or hyperoxic lung injury [25] in animal models. Both IL-6 and GM-CSF stimulate the marrow to produce and release monocytes while the acute response cytokines, IL-1 and TNF-α, secreted in response to PM10 stimulation by AM [7,13] induce the production of monocytic chemoattractants such as MCP-1 [20,21,26-29]. "
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    ABSTRACT: Studies from our laboratory have shown that human alveolar macrophages (AM) and bronchial epithelial cells (HBEC) exposed to ambient particles (PM10) in vitro increase their production of inflammatory mediators and that supernatants from PM10-exposed cells shorten the transit time of monocytes through the bone marrow and promote their release into the circulation. The present study concerns co-culture of AM and HBEC exposed to PM10 (EHC-93) and the production of mediators involved in monocyte kinetics measured at both the mRNA and protein levels. The experiments were also designed to determine the role of the adhesive interaction between these cells via the intercellular adhesion molecule (ICAM)-1 in the production of these mediators. AM/HBEC co-cultures exposed to 100 microg/ml of PM10 for 2 or 24 h increased their levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), M-CSF, macrophage inflammatory protein (MIP)-1beta, monocyte chemotactic protein (MCP)-1, interleukin (IL)-6 and ICAM-1 mRNA, compared to exposed AM or HBEC mono-cultures, or control non-exposed co-cultures. The levels of GM-CSF, M-CSF, MIP-1beta and IL-6 increased in co-cultured supernatants collected after 24 h exposure compared to control cells (p < 0.05). There was synergy between AM and HBEC in the production of GM-CSF, MIP-1beta and IL-6. But neither pretreatment of HBEC with blocking antibodies against ICAM-1 nor cross-linking of ICAM-1 on HBEC blocked the PM10-induced increase in co-culture mRNA expression. We conclude that an ICAM-1 independent interaction between AM and HBEC, lung cells that process inhaled particles, increases the production and release of mediators that enhance bone marrow turnover of monocytes and their recruitment into tissues. We speculate that this interaction amplifies PM10-induced lung inflammation and contributes to both the pulmonary and systemic morbidity associated with exposure to air pollution.
    Respiratory research 02/2005; 6(1):87. DOI:10.1186/1465-9921-6-87 · 3.09 Impact Factor
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