Imperial College London
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DrChristopherRhodes

Faculty of Medicine, National Heart & Lung Institute

Reader in Pulmonary Vascular Disease
 
 
 
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Contact

 

+44 (0)20 7594 7638c.rhodes07

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Frid:2019:10.1164/rccm.201903-0591OC,
author = {Frid, MG and McKeon, BA and Thurman, JM and Maron, BA and Li, M and Zhang, H and Kumar, S and Sullivan, T and Laskowsky, J and Fini, MA and Hu, S and Tuder, RM and Gandjeva, A and Wilkins, MR and Rhodes, CJ and Ghataorhe, P and Leopold, JA and Wang, R-S and Holers, VM and Stenmark, KR},
doi = {10.1164/rccm.201903-0591OC},
journal = {American Journal of Respiratory and Critical Care Medicine},
pages = {224--239},
title = {Immunoglobulin-driven complement activation regulates pro-inflammatory remodeling in pulmonary hypertension.},
url = {http://dx.doi.org/10.1164/rccm.201903-0591OC},
volume = {201},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - RATIONALE: Pulmonary (arterial) hypertension (PH/PAH) is a life-threatening cardiopulmonary disorder where inflammation and immunity have emerged as critical early pathogenic elements. Although pro-inflammatory processes in PH/PAH are the focus of extensive investigation, the initiating mechanisms remain elusive. OBJECTIVES: We tested whether activation of the complement cascade is critical in regulating pro-inflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH, and can serve as a prognostic biomarker of outcome in human PAH. METHODS: We employed immunostaining of lung tissues from experimental PH models and PAH patients; analyses of genetic murine models lacking specific complement components or circulating immunoglobulins; cultured human pulmonary adventitial fibroblasts; and network medicine analysis of a biomarker risk panel from plasma of PAH patients. MEASUREMENTS AND MAIN RESULTS: Pulmonary perivascular-specific activation of the complement cascade was identified as a consistent critical determinant of PH/PAH in experimental animal models and humans. In experimental hypoxic PH, pro-inflammatory and pro-proliferative responses were complement (Alternative pathway and C5)-dependent, and immunoglobulins, particularly IgG, were critical for activation of the complement cascade. We identify Csf2/GM-CSF as a primary complement-dependent inflammatory mediator. Furthermore, using network medicine analysis of a biomarker risk panel from plasma of PAH patients, we demonstrate that complement signaling can serve as a prognostic factor for clinical outcome in PAH. CONCLUSIONS: The present study establishes immunoglobulin-driven dysregulated complement activation as a critical pathobiological mechanism regulating pro-inflammatory/pro-proliferative processes in the initiation of experimental hypoxic PH, and demonstrates complement signaling as a critical determinant of clinical outcome of in PAH.
AU  - Frid,MG
AU  - McKeon,BA
AU  - Thurman,JM
AU  - Maron,BA
AU  - Li,M
AU  - Zhang,H
AU  - Kumar,S
AU  - Sullivan,T
AU  - Laskowsky,J
AU  - Fini,MA
AU  - Hu,S
AU  - Tuder,RM
AU  - Gandjeva,A
AU  - Wilkins,MR
AU  - Rhodes,CJ
AU  - Ghataorhe,P
AU  - Leopold,JA
AU  - Wang,R-S
AU  - Holers,VM
AU  - Stenmark,KR
DO  - 10.1164/rccm.201903-0591OC
EP  - 239
PY  - 2019///
SN  - 1073-449X
SP  - 224
TI  - Immunoglobulin-driven complement activation regulates pro-inflammatory remodeling in pulmonary hypertension.
T2  - American Journal of Respiratory and Critical Care Medicine
UR  - http://dx.doi.org/10.1164/rccm.201903-0591OC
UR  - https://www.ncbi.nlm.nih.gov/pubmed/31545648
UR  - https://www.atsjournals.org/doi/10.1164/rccm.201903-0591OC
UR  - http://hdl.handle.net/10044/1/94212
VL  - 201
ER  -
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