Abstract
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the PI3K/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained PI3K activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates IPF, in a murine model of bleomycin-induced pulmonary fibrosis (BIPF). We found that myeloid PTEN deficient mice (PTENMyKO), after induction of BIPF, exhibit increased TGF-β1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTENMyKO mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-α in PTENMyKO mice during BIPF. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options
We found that col Iα1 and colIα2 mRNA expression levels were increased in mice 7d post BLM treatment compared to treatment-naive mice and that the expression was enhanced in the PTENMyKO mice
In this study we show that phosphatase and tensin homolog (PTEN) deficiency in myeloid cells drives the development and the progression of pulmonary fibrosis induced by the administration of BLM
Summary
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options. We found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-α in PTENMyKO mice during BIPF This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis. Inflammation during fibrosis is a double-edged sword as a strong early inflammatory response is thought to promote fibrosis, whereas late onset inflammation instead inhibits the pro-fibrotic outcome[1].Since the time point of onset of reparative inflammation is crucial for its effect, it is important to understand the detailed mechanism of the disease progression in order to design new interventional treatment strategies. Targeting IL-6 by means of antibodies reduces collagen deposition and leukocyte infiltration in BLM induced dermal fibrosis[10] and via trans signalling IL-6 promotes collagen I synthesis in dermal fibroblasts[12]
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