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

Abstract

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-a 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-a 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.

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

“…We have shown, using an APR-null mouse model (lacking both hepatic STAT3 and RelA), that liver activation is required for survival, hepatoprotection, and maximal pulmonary inflammation during an E. coli pneumonia (23), as well as systemic defense and opsonophagocytosis during pneumococcal pneumonia (24). The common clinical observation that sepsis is frequently followed by pneumonia (5,6,8) raises the question of whether or how a preexisting liver response alters pneumonia susceptibility, for better or for worse.…”

“…Indeed, liver-derived acute-phase proteins are diverse in number and function, promoting a wide variety of immunological processes. Previous studies from our laboratory have implicated the APR in the activation of airspace macrophages during pneumonia (23), and a multitude of APPs have been shown to activate macrophages (61)(62)(63)(64). Also, pentraxins such as SAP and C-reactive protein (CRP) engage numerous receptors capable of activating macrophages (and other cells), which can promote ROS generation (65,66).…”

“…infection with 1 ϫ 10 6 CFU of Escherichia coli (Fig. 1A) (serotype 06:K2:H1; ATCC 19138), as previously described by our laboratory (23). For i.t.…”

“…Induced by the host defense cytokines tumor necrosis factor alpha (TNF-␣), interleukin-1 (IL-1), and IL-6 (20), the APR is characterized by significant changes in circulating levels of acute-phase proteins (APPs) (19,21,22). While it is well appreciated that sepsis can cause pulmonary immunosuppression and pneumonia susceptibility (5, 7-15), it is unclear whether or how preexisting liver activation (i.e., sepsis-induced APR) modulates subsequent responses to local lung infections.Signal transducer and activator of transcription-3 (STAT3) is one of two transcription factors (along with NF-B RelA) required for induction of a strong hepatic APR during pneumonia (23)(24)(25). Several lines of evidence implicate beneficial roles for liver-derived APPs during pneumonia (26)(27)(28)(29).…”

“…Signal transducer and activator of transcription-3 (STAT3) is one of two transcription factors (along with NF-B RelA) required for induction of a strong hepatic APR during pneumonia (23)(24)(25). Several lines of evidence implicate beneficial roles for liver-derived APPs during pneumonia (26)(27)(28)(29).…”