Pneumonia and sepsis are integrally linked, each representing a major public health concern, and each significantly increasing the likelihood that the other will occur. However, the host mechanisms guiding this dangerous interaction remain speculative. The acute phase response is a common feature of both pneumonia and sepsis, involving robust remodeling of the hepatic transcriptome followed by mobilization of numerous liver-derived acute phase proteins, several of which are known clinical biomarkers of disease severity. The net physiological significance of these integrated acute phase changes is only beginning to be understood. We recently showed that pneumonia elicits a robust acute phase response that is functionally relevant and highly dependent on hepatocyte expression of the transcription factors NF-?B RelA and STAT3. Using hepatocyte- targeted mouse models, our preliminary studies implicate the liver as a gatekeeper that compartmentalizes infection during sepsis or pneumonia, reducing the likelihood that one will promote the other. Specifically, we now have evidence that: 1) STAT3-dependent liver responses to endotoxemia protect against pneumonia susceptibility, associated with expression of iron-regulating acute phase proteins; and 2) RelA-dependent liver responses during pneumonia protect against sepsis outcomes, including liver failure and bacteremia. Here we propose the central hypothesis that hepatocyte transcriptional responses are critical for limiting the deleterious interactions between pneumonia and sepsis. This hypothesis will be tested by pursuing the following three aims:
Aim 1) Test the hypothesis that hepatocyte STAT3 activation counters sepsis-induced pneumonia susceptibility by promoting iron withdrawal and lung mucosal defense;
Aim 2) Test the hypothesis that hepatocyte RelA activation counters pneumonia-induced sepsis by preventing programmed cell death, organ failure, and bacteremia;
and Aim 3) Test the hypothesis that STAT3 and RelA are each essential for human hepatocytes to elicit acute phase gene programs that direct alveolar macrophage responses. Studies designed to address these aims will use a multidisciplinary approach to comprehensively determine the mechanistic basis of liver-derived protection at the interface of pneumonia and sepsis. These investigations will be the first to directly interrogate liver function in this capacity, possibly revealing important determinants of clinical outcome in patients with pneumonia or sepsis.
Sepsis and pneumonia frequently arise from severe infections, together and individually representing major public health concerns. These conditions are integrally linked, with one strongly increasing the likelihood of the other, ultimately increasing the risk of organ injury and poor clinical outcome. Sepsis and pneumonia also elicit a robust hepatic response, and the goal of our proposed studies will be to determine whether and how liver responses control the harmful collaboration between these two devastating clinical scenarios.
|Quinton, Lee J (2018) C-rac-king the Code of Smoke-induced Pneumonia Susceptibility. Am J Respir Crit Care Med 198:1246-1248|
|Smith, N Ms; Wasserman, G A; Coleman, F T et al. (2018) Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia. Mucosal Immunol 11:220-235|
|Quinton, Lee J; Walkey, Allan J; Mizgerd, Joseph P (2018) Integrative Physiology of Pneumonia. Physiol Rev 98:1417-1464|
|Wasserman, Gregory A; Szymaniak, Aleksander D; Hinds, Anne C et al. (2017) Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells. J Clin Invest 127:3866-3876|
|Coleman, Fadie T; Blahna, Matthew T; Kamata, Hirofumi et al. (2017) Capacity of Pneumococci to Activate Macrophage Nuclear Factor ?B: Influence on Necroptosis and Pneumonia Severity. J Infect Dis 216:425-435|
|Kozlowski, Elyse; Wasserman, Gregory A; Morgan, Marcos et al. (2017) The RNA uridyltransferase Zcchc6 is expressed in macrophages and impacts innate immune responses. PLoS One 12:e0179797|
|Traber, Katrina E; Symer, Elise M; Allen, Eri et al. (2017) Myeloid-epithelial cross talk coordinates synthesis of the tissue-protective cytokine leukemia inhibitory factor during pneumonia. Am J Physiol Lung Cell Mol Physiol 313:L548-L558|
|Jacob, Anjali; Morley, Michael; Hawkins, Finn et al. (2017) Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21:472-488.e10|