title: Silencing Bruton's tyrosine kinase in alveolar neutrophils protects mice from LPS/immune complex-induced acute lung injury.
abstract: Previous observations made by our laboratory indicate that Bruton's tyrosine kinase (Btk) may play an important role in the pathophysiology of local inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We have shown that there is cross talk between FcγRIIa and TLR4 in alveolar neutrophils from patients with ALI/ARDS and that Btk mediates the molecular cooperation between these two receptors. To study the function of Btk in vivo we have developed a unique two-hit model of ALI: LPS/immune complex (IC)-induced ALI. Furthermore, we conjugated F(ab)2 fragments of anti-neutrophil antibodies (Ly6G1A8) with specific siRNA for Btk to silence Btk specifically in alveolar neutrophils. It should be stressed that we are the first group to perform noninvasive transfections of neutrophils, both in vitro and in vivo. Importantly, our present findings indicate that silencing Btk in alveolar neutrophils has a dramatic protective effect in mice with LPS/IC-induced ALI, and that Btk regulates neutrophil survival and clearance of apoptotic neutrophils in this model. In conclusion, we put forward a hypothesis that Btk-targeted neutrophil specific therapy is a valid goal of research geared toward restoring homeostasis in lungs of patients with ALI/ARDS.
authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas; Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland;
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Krupa
authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas; Department of Immunology and Infectious Biology, University of Lodz, Lodz, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Fol
authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Moshiur
authors.initials: M
authors.lastname: Rahman
authors.affiliation: Department of Molecular and Cellular Physiology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana;
authors.forename: Karen Y
authors.initials: KY
authors.lastname: Stokes
authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Jon M
authors.initials: JM
authors.lastname: Florence
authors.affiliation: Department of Molecular and Cellular Physiology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana;
authors.forename: Igor L
authors.initials: IL
authors.lastname: Leskov
authors.affiliation: Department of Molecular and Cellular Physiology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana;
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Khoretonenko
authors.affiliation: Departments of Medicine and Anesthesia, University of California, San Francisco, California; and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Departments of Medicine and Anesthesia, University of California, San Francisco, California; and.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Liu
authors.affiliation: Departments of Medicine and Anesthesia, University of California, San Francisco, California; and.
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Amy
authors.initials: A
authors.lastname: Tvinnereim
authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Rosenfield
authors.affiliation: Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas; anna.kurdowska@uthct.edu.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kurdowska
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000936:Antigen-Antibody Complex / Q000633:toxicity*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000473:pathology; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; C445323:FCGR2A protein, human; D008070:Lipopolysaccharides; D017452:Receptors, IgG; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse
keywords: ALI; Btk; LPS; immune complex; neutrophil
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