Published Papers - YAMAMOTO KAZUKO

Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia

Katrina E. Traber, Kristie L. Hilliard, Eri Allen, Gregory A. Wasserman, Kazuko Yamamoto, Matthew R. Jones, Joseph P. Mizgerd, Lee J. Quinton

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY ( AMER THORACIC SOC )  53 ( 4 ) 479 - 488   2015.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Acute bacterial pneumonia is a significant public health concern worldwide. Understanding the signals coordinating lung innate immunity may foster the development of therapeutics that limit tissue damage and promote host defense. We have previously shown that lung messenger RNA expression of the IL-6 family cytokine oncostatin-M (OSM) is significantly elevated in response to bacterial stimuli. However, its physiological significance during pneumonia is unknown. Here we demonstrate that OSM is rapidly increased in the airspaces of mice after pulmonary infection with Escherichia coli. Neutralization of OSM caused a substantial decrease in airspace neutrophils and macrophages. OSM blockade also caused a marked reduction in lung chemokine (C-X-C motif) ligand (CXCL) 5 expression, whereas other closely related neutrophil chemokines, CXCL1 and CXCL2, were unaffected. Intratracheal administration of recombinant OSM was sufficient to recapitulate the effect on CXCL5 induction, associated with robust activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor. Cell sorting revealed that OSM effects were specific to lung epithelial cells, including a positive feedback loop in which OSM may facilitate expression of its own receptor. Finally, in vitro studies demonstrated that STAT3 was required for maximal OSM-induced CXCL5 expression. These studies demonstrate a novel role for OSM during pneumonia as an important signal to epithelial cells for chemokine induction mediating neutrophil recruitment.

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The lung-liver axis facilitates pulmonary innate immunity and hepatoprotection during pneumonia.

Hilliard KL, Allen E, Traber KE, Yamamoto K, Stauffer NM, Wasserman GA, Jones MR, Mizgerd JP, Quinton LJ

American journal of respiratory cell and molecular biology   53 ( 3 ) 479 - 488   2015.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia

Hilliard KL, Allen E, Traber KE, Yamamoto K, Stauffer NM, Wasserman GA, Jones MR, Mizgerd JP, Quinton LJ

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY ( AMER THORACIC SOC )  53 ( 3 ) 378 - 390   2015.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The hepatic acute-phase response (APR), stimulated by injury or inflammation, is characterized by significant changes in circulating acute-phase protein (APP) concentrations. Although individual functions of liver-derived APPs are known, the net consequence of APP changes is unclear. Pneumonia, which induces the APR, causes an inflammatory response within the airspaces that is coordinated largely by alveolar macrophages and is typified by cytokine production, leukocyte recruitment, and plasma extravasation, the latter of which may enable delivery of hepatocyte-derived APPs to the infection site. To determine the functional significance of the hepatic APR during pneumonia, we challenged APR-null mice lacking hepatocyte signal transducer and activator of transcription 3 (STAT3) and v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) with Escherichia coli in the airspaces. APR-null mice displayed ablated APP induction, significantly increased mortality, liver injury and apoptosis, and a trend toward increased bacterial burdens. TNF-alpha neutralization reversed hepatotoxicity, but not mortality, suggesting that APR-dependent survival is not solely due to hepatoprotection. After a milder (nonlethal) E. coli infection, hepatocyte-specific mutations decreased APP concentrations and pulmonary inflammation in bronchoalveolar lavage fluid. Cytokine expression in airspace macrophages, but not other airspace or circulating cells, was significantly dependent on APP extravasation into the alveoli. These data identify a novel signaling axis whereby the liver response enhances macrophage activation and pulmonary inflammation during pneumonia. Although hepatic acute-phase changes directly curb injury induced by TNF-alpha in the liver itself, APPs downstream of these same signals promote survival in association with innate immunity in the lungs, thus demonstrating a critical role for the lung-liver axis during pneumonia.

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