Modulation of the HGF/c-Met Axis Impacts Prolonged Hematopoietic Progenitor Mobilization Following Trauma and Chronic Stress

BACKGROUND:Trauma and hemorrhagic shock trigger mobilization of hematopoietic progenitor cells (HPC) from bone marrow to peripheral blood. Hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-Met), matrix metallopeptidase 9 (MMP-9), and corticosterone regulate this mobilization process. We...

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Published in:Shock (Augusta, Ga.) Ga.), 2020-10, Vol.54 (4), p.482-487
Main Authors: Loftus, Tyler J., Kannan, Kolenkode B., Mira, Juan C., Brakenridge, Scott C., Efron, Philip A., Mohr, Alicia M.
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container_start_page 482
container_title Shock (Augusta, Ga.)
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creator Loftus, Tyler J.
Kannan, Kolenkode B.
Mira, Juan C.
Brakenridge, Scott C.
Efron, Philip A.
Mohr, Alicia M.
description BACKGROUND:Trauma and hemorrhagic shock trigger mobilization of hematopoietic progenitor cells (HPC) from bone marrow to peripheral blood. Hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-Met), matrix metallopeptidase 9 (MMP-9), and corticosterone regulate this mobilization process. We hypothesized that beta-blockade with propranolol and sympathetic outflow inhibition with clonidine following trauma and chronic stress would decrease hematopoietic progenitor cell mobilization. METHODS:Sprague-Dawley rats were randomized to undergo three models of injury and stresslung contusion, LC plus hemorrhagic shock (LCHS), or LCHS plus chronic restraint stress for 2 h daily (LCHS/CS). Propranolol and clonidine were administered by daily intraperitoneal injection until sacrifice on day seven. Bone marrow HGF, c-Met, and MMP-9 were measured by real-time PCR. Plasma corticosterone was measured by ELISA. Percentage HPC in peripheral blood was measured by flow cytometry. RESULTS:Propranolol and clonidine significantly decreased bone marrow MMP-9 expression, plasma corticosterone levels, and HPC mobilization, and significantly increased hemoglobin levels. HPC mobilization was greatest following LCHS/CS (5.4 ± 1.8) and was significantly decreased by propranolol (2.2 ± 0.9, P 
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Hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-Met), matrix metallopeptidase 9 (MMP-9), and corticosterone regulate this mobilization process. We hypothesized that beta-blockade with propranolol and sympathetic outflow inhibition with clonidine following trauma and chronic stress would decrease hematopoietic progenitor cell mobilization. METHODS:Sprague-Dawley rats were randomized to undergo three models of injury and stresslung contusion, LC plus hemorrhagic shock (LCHS), or LCHS plus chronic restraint stress for 2 h daily (LCHS/CS). Propranolol and clonidine were administered by daily intraperitoneal injection until sacrifice on day seven. Bone marrow HGF, c-Met, and MMP-9 were measured by real-time PCR. Plasma corticosterone was measured by ELISA. Percentage HPC in peripheral blood was measured by flow cytometry. RESULTS:Propranolol and clonidine significantly decreased bone marrow MMP-9 expression, plasma corticosterone levels, and HPC mobilization, and significantly increased hemoglobin levels. HPC mobilization was greatest following LCHS/CS (5.4 ± 1.8) and was significantly decreased by propranolol (2.2 ± 0.9, P &lt; 0.001) and clonidine (1.7 ± 0.5, P &lt; 0.001). Hemoglobin (g/dL) was lowest following LCHS/CS (12.3 ± 1.2) and was significantly increased by propranolol (13.7 ± 0.4, P = 0.022) and clonidine (14.1 ± 1.1, P &lt; 0.001). CONCLUSIONS:Severe injury was associated with increased bone marrow HGF, c-Met, and MMP-9, circulating corticosterone, HPC mobilization, and persistent anemia. Attenuating the neuroendocrine response to injury and stress with propranolol and clonidine reduced MMP-9 expression, corticosterone levels, HPC mobilization, and the degree of anemia.</description><identifier>ISSN: 1073-2322</identifier><identifier>EISSN: 1540-0514</identifier><identifier>DOI: 10.1097/SHK.0000000000001506</identifier><identifier>PMID: 31904616</identifier><language>eng</language><publisher>United States: Lippincott Williams &amp; Wilkins</publisher><ispartof>Shock (Augusta, Ga.), 2020-10, Vol.54 (4), p.482-487</ispartof><rights>Lippincott Williams &amp; Wilkins</rights><rights>2020 by the Shock Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5026-9a6f2dc4b465bc8b95390d81a0d478669b655fe6d7fe28f9b53764d6627596a3</citedby><cites>FETCH-LOGICAL-c5026-9a6f2dc4b465bc8b95390d81a0d478669b655fe6d7fe28f9b53764d6627596a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31904616$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Loftus, Tyler J.</creatorcontrib><creatorcontrib>Kannan, Kolenkode B.</creatorcontrib><creatorcontrib>Mira, Juan C.</creatorcontrib><creatorcontrib>Brakenridge, Scott C.</creatorcontrib><creatorcontrib>Efron, Philip A.</creatorcontrib><creatorcontrib>Mohr, Alicia M.</creatorcontrib><title>Modulation of the HGF/c-Met Axis Impacts Prolonged Hematopoietic Progenitor Mobilization Following Trauma and Chronic Stress</title><title>Shock (Augusta, Ga.)</title><addtitle>Shock</addtitle><description>BACKGROUND:Trauma and hemorrhagic shock trigger mobilization of hematopoietic progenitor cells (HPC) from bone marrow to peripheral blood. Hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-Met), matrix metallopeptidase 9 (MMP-9), and corticosterone regulate this mobilization process. We hypothesized that beta-blockade with propranolol and sympathetic outflow inhibition with clonidine following trauma and chronic stress would decrease hematopoietic progenitor cell mobilization. METHODS:Sprague-Dawley rats were randomized to undergo three models of injury and stresslung contusion, LC plus hemorrhagic shock (LCHS), or LCHS plus chronic restraint stress for 2 h daily (LCHS/CS). Propranolol and clonidine were administered by daily intraperitoneal injection until sacrifice on day seven. Bone marrow HGF, c-Met, and MMP-9 were measured by real-time PCR. Plasma corticosterone was measured by ELISA. Percentage HPC in peripheral blood was measured by flow cytometry. RESULTS:Propranolol and clonidine significantly decreased bone marrow MMP-9 expression, plasma corticosterone levels, and HPC mobilization, and significantly increased hemoglobin levels. HPC mobilization was greatest following LCHS/CS (5.4 ± 1.8) and was significantly decreased by propranolol (2.2 ± 0.9, P &lt; 0.001) and clonidine (1.7 ± 0.5, P &lt; 0.001). Hemoglobin (g/dL) was lowest following LCHS/CS (12.3 ± 1.2) and was significantly increased by propranolol (13.7 ± 0.4, P = 0.022) and clonidine (14.1 ± 1.1, P &lt; 0.001). CONCLUSIONS:Severe injury was associated with increased bone marrow HGF, c-Met, and MMP-9, circulating corticosterone, HPC mobilization, and persistent anemia. Attenuating the neuroendocrine response to injury and stress with propranolol and clonidine reduced MMP-9 expression, corticosterone levels, HPC mobilization, and the degree of anemia.</description><issn>1073-2322</issn><issn>1540-0514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNqFks1u1DAUhSNERUvhDRDykk1a_yfeIFUjplPREUidveUkNxODEw-2w7SIhydh2qqwAC98r3zPd2zpOMveEHxGsCrOb1Yfz_CTRQSWz7ITIjjOsSD8-dTjguWUUXqcvYzxC8aUM1W8yI4ZUZhLIk-yn2vfjM4k6wfkW5Q6QKvL5XmdryGhi1sb0VW_M3WK6HPwzg9baNAKepP8zltItp7PtzDY5ANa-8o6--PgtvTO-b0dtmgTzNgbZIYGLbrghwm6SQFifJUdtcZFeH1fT7PN8sNmscqvP11eLS6u81pgKnNlZEubmldciqouKyWYwk1JDG54UUqpKilEC7IpWqBlqyrBCskbKWkhlDTsNHt_sN2NVQ9NDUMKxuldsL0Jd9obq_-cDLbTW_9dF4xRjslk8O7eIPhvI8SkextrcM4M4MeoKWNMMaroLOUHaR18jAHax2sI1nNuespN_53bhL19-sRH6CGoSVAeBHvvEoT41Y17CLoD41L3P2_-DxT__hUlzSmmmMxQPm8l-wXp8rXh</recordid><startdate>20201001</startdate><enddate>20201001</enddate><creator>Loftus, Tyler J.</creator><creator>Kannan, Kolenkode B.</creator><creator>Mira, Juan C.</creator><creator>Brakenridge, Scott C.</creator><creator>Efron, Philip A.</creator><creator>Mohr, Alicia M.</creator><general>Lippincott Williams &amp; Wilkins</general><general>by the Shock Society</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20201001</creationdate><title>Modulation of the HGF/c-Met Axis Impacts Prolonged Hematopoietic Progenitor Mobilization Following Trauma and Chronic Stress</title><author>Loftus, Tyler J. ; Kannan, Kolenkode B. ; Mira, Juan C. ; Brakenridge, Scott C. ; Efron, Philip A. ; Mohr, Alicia M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5026-9a6f2dc4b465bc8b95390d81a0d478669b655fe6d7fe28f9b53764d6627596a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Loftus, Tyler J.</creatorcontrib><creatorcontrib>Kannan, Kolenkode B.</creatorcontrib><creatorcontrib>Mira, Juan C.</creatorcontrib><creatorcontrib>Brakenridge, Scott C.</creatorcontrib><creatorcontrib>Efron, Philip A.</creatorcontrib><creatorcontrib>Mohr, Alicia M.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Shock (Augusta, Ga.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Loftus, Tyler J.</au><au>Kannan, Kolenkode B.</au><au>Mira, Juan C.</au><au>Brakenridge, Scott C.</au><au>Efron, Philip A.</au><au>Mohr, Alicia M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of the HGF/c-Met Axis Impacts Prolonged Hematopoietic Progenitor Mobilization Following Trauma and Chronic Stress</atitle><jtitle>Shock (Augusta, Ga.)</jtitle><addtitle>Shock</addtitle><date>2020-10-01</date><risdate>2020</risdate><volume>54</volume><issue>4</issue><spage>482</spage><epage>487</epage><pages>482-487</pages><issn>1073-2322</issn><eissn>1540-0514</eissn><abstract>BACKGROUND:Trauma and hemorrhagic shock trigger mobilization of hematopoietic progenitor cells (HPC) from bone marrow to peripheral blood. Hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-Met), matrix metallopeptidase 9 (MMP-9), and corticosterone regulate this mobilization process. We hypothesized that beta-blockade with propranolol and sympathetic outflow inhibition with clonidine following trauma and chronic stress would decrease hematopoietic progenitor cell mobilization. METHODS:Sprague-Dawley rats were randomized to undergo three models of injury and stresslung contusion, LC plus hemorrhagic shock (LCHS), or LCHS plus chronic restraint stress for 2 h daily (LCHS/CS). Propranolol and clonidine were administered by daily intraperitoneal injection until sacrifice on day seven. Bone marrow HGF, c-Met, and MMP-9 were measured by real-time PCR. Plasma corticosterone was measured by ELISA. Percentage HPC in peripheral blood was measured by flow cytometry. RESULTS:Propranolol and clonidine significantly decreased bone marrow MMP-9 expression, plasma corticosterone levels, and HPC mobilization, and significantly increased hemoglobin levels. HPC mobilization was greatest following LCHS/CS (5.4 ± 1.8) and was significantly decreased by propranolol (2.2 ± 0.9, P &lt; 0.001) and clonidine (1.7 ± 0.5, P &lt; 0.001). Hemoglobin (g/dL) was lowest following LCHS/CS (12.3 ± 1.2) and was significantly increased by propranolol (13.7 ± 0.4, P = 0.022) and clonidine (14.1 ± 1.1, P &lt; 0.001). CONCLUSIONS:Severe injury was associated with increased bone marrow HGF, c-Met, and MMP-9, circulating corticosterone, HPC mobilization, and persistent anemia. Attenuating the neuroendocrine response to injury and stress with propranolol and clonidine reduced MMP-9 expression, corticosterone levels, HPC mobilization, and the degree of anemia.</abstract><cop>United States</cop><pub>Lippincott Williams &amp; Wilkins</pub><pmid>31904616</pmid><doi>10.1097/SHK.0000000000001506</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
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