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Liver-dependent lung remodeling in the wake of systemic inflammation shapes responses to secondary infection

ABSTRACT: :Systemic duress, like that elicited by sepsis, burns or trauma, predispose patients to nosocomial pneumonia, demanding better understanding of host pathways influencing this deleterious connection. These pre-existing circumstances are capable of triggering the hepatic acute phase response (APR), which we previously demonstrated is essential for limiting susceptibility to secondary lung infections. To identify potential mechanisms underlying protection afforded by the lung-liver axis, our studies aimed to evaluate liver-dependent lung reprogramming when a systemic inflammatory challenge precedes pneumonia. WT mice and APR-deficient littermates lacking hepatocyte STAT3 (hepSTAT3-/-), a transcription factor necessary for full APR initiation, were challenged intraperitoneally with LPS to induce endotoxemia. After 18h, pneumonia was induced by intratracheal E. coli instillation. Endotoxemia elicited significant transcriptional alterations in the lungs of WT and hepSTAT3-/- mice, with nearly 2,000 differentially expressed genes between genotypes. The gene signatures revealed exaggerated immune activity in the lungs of hepSTAT3-/- mice, which were compromised in their capacity to launch additional cytokine responses to secondary infection. Proteomics revealed substantial liver-dependent modifications in the airspaces of pneumonic mice, implicating a network of dispatched liver-derived mediators influencing lung homeostasis. These results indicate that following systemic inflammation, liver acute phase changes dramatically remodel the lungs, resulting in a modified landscape for any stimuli encountered thereafter. Based on the established vulnerability of hepSTAT3-/- mice to secondary lung infections, we believe that intact liver function is critical for maintaining the immunological responsiveness of the lungs. Further studies are needed to confirm whether and how such lung changes directly influence pneumonia susceptibility.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bronchoalveolar Lavage

DISEASE(S): Pneumonia

SUBMITTER: TuKiet Lam

LAB HEAD: TuKiet Lam

PROVIDER: PXD024663 | Pride | 2021-07-23

REPOSITORIES: Pride

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			Action	DRS
	LF18-074_Odom_rnk10_iso2_F514817.xml	Xml
	LF18-074_Odom_rnk10_iso2_F514817_Results_PRIDE_Export.MSMS.mgf	Mgf
	OTF19-1059_Odom_3_19_18_2.raw	Raw
	OTF19-1059_Odom_3_19_18_3.raw	Raw
	OTF19-1064_Odom_3_19_18_2.raw	Raw

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Project description:Systemic duress such as that elicited by sepsis, burns or trauma predispose patients to nosocomial pneumonia, demanding a better understanding of host pathways influencing this connection. These systemic challenges are also capable of triggering the hepatic acute phase response (APR), an event that we have previously demonstrated as essential for limiting susceptibility to secondary lung infections. In an effort to identify potential mechanisms underlying protection afforded by the lung-liver axis, our current studies aimed to comprehensively evaluate liver-dependent lung reprogramming following a systemic inflammatory challenge with endotoxemia followed by pneumonia. To do so, WT mice and APR-deficient littermates lacking hepatocyte STAT3 (hepSTAT3-/-), a transcription factor necessary for full APR initiation, were challenged intraperitoneally with LPS to induce endotoxemia. After 18h, pneumonia was induced by an intratracheal E. coli instillation. Lung transcriptional profiling, airspace proteomics, and additional validation measures were assessed after endotoxemia with or without a subsequent challenge with pneumonia in order to achieve an unbiased assessment of lung immune activity in the presence and absence of an intact liver response. In WT mice, endotoxemia elicited robust transcriptional changes in the lungs, with nearly 2,000 differentially expressed genes when comparing WT and hepSTAT3-/- mice. The resulting gene signatures revealed highly exaggerated immune activity in the lungs of hepSTAT3-/- mice, which were compromised in their capacity to launch additional cytokine responses to secondary infection. Proteomics also revealed substantial liver-dependent modifications in the airspaces of pneumonic mice, implicating a network of dispatched liver-derived mediators influencing lung homeostasis. These results indicate that following a systemic inflammatory event, liver acute phase changes dramatically remodel the lungs, resulting in a modified landscape for any stimuli encountered thereafter. Based on the known vulnerability of hepSTAT3-/- mice to secondary lung infections, we believe that intact liver function is critical for maintaining the immunological responsiveness of the lungs. However, further studies are needed to confirm whether and how such lung changes directly influence pneumonia susceptibility.

Project description:Vaccination reduces morbidity and mortality from pneumonia but its effect on the tissue-level response to infection is still poorly understood. We evaluated pneumonia disease progression, acute phase response and lung gene expression profiles in mice inoculated intranasally with virulent gram-positive Streptococcus pneumoniae serotype (ST) 3, with and without prior immunization with pneumococcal polysaccharide ST 3 (PPS3), or co-immunization with PPS3 and with a low dose of lipopolysaccharide (LPS). Pneumonia severity was assessed in the acute phase, 5, 12, 24 and 48 h post-inoculation (p.i.) and the resolution phase of 7 days p.i. Primary PPS3 specific antibody production was upregulated and IgM binding to pneumococci increased in PPS3-immunized mice. Immunizations with PPS3 or PPS3 + LPS decreased bacterial recovery the lung and blood at 24 and 48 h and increased survival. Microarray analysis of whole lung RNA revealed significant changes in the acute phase protein serum amyloid A (SAA) between noninfected and infected mice, which were attenuated by immunization. SAA transcripts were higher in the liver and lungs of infected controls, and SAA protein was elevated in serum, but decreased in PPS3-immunized mice. Thus, during a virulent pneumonia infection, prior immunization with PPS3 in an IgM-dependent manner as well as co-immunization with PPS3 + LPS attenuated pneumonia severity and promoted resolution of infection, concomitant with significant regulation of cytokine gene expression in the lungs, and acute phase proteins in the lungs, liver and serum. Each lung RNA sample represented an individual mouse, creating biological repeats for each treatment. In-vivo treatments were as follows: non-infected lung (vehicle-immunized) control (n=5), infected lung (vehicle-immunized) control at 48 hr post-inoculation (n=5), PPS3 and LPS co-immunized lung at 48 hr post-inoculation (n=4) and PPS3 and LPS co-immunized lung at 7 days post-inoculation (n=4).

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Liver-dependent lung remodeling in the wake of systemic inflammation shapes responses to secondary infection

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