title: Sustained PI3K Activation exacerbates BLM-induced Lung Fibrosis via activation of pro-inflammatory and pro-fibrotic pathways.
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 (PTEN(MyKO)), 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 PTEN(MyKO) 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 PTEN(MyKO) 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.
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Julia Barbara
authors.initials: JB
authors.lastname: Kral
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Mario
authors.initials: M
authors.lastname: Kuttke
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Waltraud Cornelia
authors.initials: WC
authors.lastname: Schrottmaier
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Birnecker
authors.affiliation: CEMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical Univ. Vienna, Austria.
authors.forename: Joanna
authors.initials: J
authors.lastname: Warszawska
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Wernig
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Hannah
authors.initials: H
authors.lastname: Paar
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salzmann
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Emine
authors.initials: E
authors.lastname: Sahin
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Julia Stefanie
authors.initials: JS
authors.lastname: Brunner
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Österreicher
authors.affiliation: CEMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical Univ. Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Alice
authors.initials: A
authors.lastname: Assinger
authors.affiliation: Institute of Physiology, Center for Physiology &Pharmacology, Medical Univ. Vienna, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
mesh_terms: D000818:Animals; D001761:Bleomycin; D015153:Blotting, Western; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000145:classification / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse