Todd W Costantini1, Raul Coimbra2, Jessica L Weaver3, Brian P Eliceiri3. 1. Division of Trauma, Surgical Critical Care, Burns and Acute Care Surgery, Department of Surgery, UC San Diego School of Medicine, San Diego, CA, USA. tcostantini@health.ucsd.edu. 2. Comparative Effectiveness and Clinical Outcomes Research Center, Riverside University Health System, Loma Linda University School of Medicine, Riverside, CA, USA. 3. Division of Trauma, Surgical Critical Care, Burns and Acute Care Surgery, Department of Surgery, UC San Diego School of Medicine, San Diego, CA, USA.
Abstract
INTRODUCTION: The CHRNA7 gene encodes the α-7 nicotinic acetylcholine receptor (α7nAchR) that regulates anti-inflammatory responses to injury; however, only humans express a variant gene called CHRFAM7A that alters the function of α7nAChR; CHRFAM7A expression predominates in bone marrow and monocytes/macrophages where the CHRFAM7A/CHRNA7 ratio is highly variable between individuals. We have previously shown in transgenic mice that CHRFAM7A increased emergency myelopoiesis from the bone marrow and monocyte/macrophage expression in lungs. MATERIALS AND METHODS: CHRFAM7A transgenic mice are compared to age- and gender-matched wild-type (WT) siblings. We utilized a model of sepsis using LPS injection to measure survival. Lung vascular permeability was measured after severe burn injury in WT vs. CHRFAM7A transgenic mice. Bone marrow CHRFAM7A expression was evaluated using adoptive transfer of CHRFAM7A transgenic bone marrow into WT mice. RESULTS: Here, we demonstrate that CHRFAM7A expression results in an anti-inflammatory phenotype with an improved survival to LPS and decreased acute lung injury in a severe cutaneous burn model compared to WT. CONCLUSIONS: These data suggest that the relative expression of CHRFAM7A may alter resiliency to injury and contribute to individual variability in the human systemic inflammatory response (SIRS) to injury.
INTRODUCTION: The CHRNA7 gene encodes the α-7 nicotinic acetylcholine receptor (α7nAchR) that regulates anti-inflammatory responses to injury; however, only humans express a variant gene called CHRFAM7A that alters the function of α7nAChR; CHRFAM7A expression predominates in bone marrow and monocytes/macrophages where the CHRFAM7A/CHRNA7 ratio is highly variable between individuals. We have previously shown in transgenic mice that CHRFAM7A increased emergency myelopoiesis from the bone marrow and monocyte/macrophage expression in lungs. MATERIALS AND METHODS: CHRFAM7A transgenic mice are compared to age- and gender-matched wild-type (WT) siblings. We utilized a model of sepsis using LPS injection to measure survival. Lung vascular permeability was measured after severe burn injury in WT vs. CHRFAM7A transgenic mice. Bone marrow CHRFAM7A expression was evaluated using adoptive transfer of CHRFAM7A transgenic bone marrow into WT mice. RESULTS: Here, we demonstrate that CHRFAM7A expression results in an anti-inflammatory phenotype with an improved survival to LPS and decreased acute lung injury in a severe cutaneous burn model compared to WT. CONCLUSIONS: These data suggest that the relative expression of CHRFAM7A may alter resiliency to injury and contribute to individual variability in the human systemic inflammatory response (SIRS) to injury.
Authors: Todd W Costantini; Michael Krzyzaniak; Gerald A Cheadle; James G Putnam; Ann-Marie Hageny; Nicole Lopez; Brian P Eliceiri; Vishal Bansal; Raul Coimbra Journal: Am J Pathol Date: 2012-06-08 Impact factor: 4.307
Authors: Todd W Costantini; Xitong Dang; Maryana V Yurchyshyna; Raul Coimbra; Brian P Eliceiri; Andrew Baird Journal: Mol Med Date: 2015-04-03 Impact factor: 6.354
Authors: Theresa W Chan; Simone Langness; Olga Cohen; Brian P Eliceiri; Andrew Baird; Todd W Costantini Journal: Inflamm Res Date: 2020-04-17 Impact factor: 4.575
Authors: Todd W Costantini; Theresa W Chan; Olga Cohen; Simone Langness; Sabrina Treadwell; Elliot Williams; Brian P Eliceiri; Andrew Baird Journal: Proc Natl Acad Sci U S A Date: 2019-04-03 Impact factor: 11.205
Authors: Carolina Martín-Sánchez; Eva Alés; Santiago Balseiro-Gómez; Gema Atienza; Francisco Arnalich; Anna Bordas; José L Cedillo; María Extremera; Arturo Chávez-Reyes; Carmen Montiel Journal: J Biol Chem Date: 2021-01-28 Impact factor: 5.157