Immunoglobulin-driven Complement Activation Regulates Proinflammatory Remodeling in Pulmonary Hypertension
| Autor: | Christopher J. Rhodes, Min Li, Aneta Gandjeva, B. Alexandre McKeon, Rui-Sheng Wang, Joshua M. Thurman, Jane A. Leopold, Hui Zhang, Rubin M. Tuder, V. Michael Holers, Sushil Kumar, Jennifer Laskowsky, Timothy M. Sullivan, Mehdi A. Fini, Samantha Hu, Bradley A. Maron, Pavandeep Ghataorhe, Maria G. Frid, Martin R. Wilkins, Kurt R. Stenmark |
|---|---|
| Přispěvatelé: | British Heart Foundation |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Respiratory System
Complement Pathway Alternative Critical Care and Intensive Care Medicine Mice 0302 clinical medicine Medicine 030212 general & internal medicine Complement Activation 11 Medical and Health Sciences Mice Knockout Pulmonary Arterial Hypertension biology Complement C5 Complement C3 Prognosis MACROPHAGE RECRUITMENT 3. Good health Hypertension Biomarker (medicine) medicine.symptom Antibody Life Sciences & Biomedicine Complement Factor B EXPRESSION Pulmonary and Respiratory Medicine FIBROBLASTS vascular remodeling Hypertension Pulmonary IMMUNE Immunoglobulins Inflammation ALTERNATIVE PATHWAY Proinflammatory cytokine 03 medical and health sciences Critical Care Medicine General & Internal Medicine Animals Humans Pulmonary Vascular Disease Science & Technology IGG business.industry hypoxia Granulocyte-Macrophage Colony-Stimulating Factor biomarkers AMPLIFICATION GM-CSF Original Articles Hypoxia (medical) medicine.disease Pulmonary hypertension Rats Complement system Disease Models Animal 030228 respiratory system inflammation Immunoglobulin G Immunology biology.protein Alternative complement pathway business |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine |
| ISSN: | 1535-4970 1073-449X |
| Popis: | Rationale: Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disorder in which inflammation and immunity have emerged as critical early pathogenic elements. Although proinflammatory processes in PH and pulmonary arterial hypertension (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 proinflammatory 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 used immunostaining of lung tissues from experimental PH models and patients with PAH, 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 patients with PAH. Measurements and Main Results: Pulmonary perivascular-specific activation of the complement cascade was identified as a consistent critical determinant of PH and PAH in experimental animal models and humans. In experimental hypoxic PH, proinflammatory and pro-proliferative responses were dependent on complement (alternative pathway and component 5), and immunoglobulins, particularly IgG, were critical for activation of the complement cascade. We identified Csf2/GM-CSF as a primary complement-dependent inflammatory mediator. Furthermore, using network medicine analysis of a biomarker risk panel from plasma of patients with PAH, we demonstrated that complement signaling can serve as a prognostic factor for clinical outcome in PAH. Conclusions: This study establishes immunoglobulin-driven dysregulated complement activation as a critical pathobiological mechanism regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and demonstrates complement signaling as a critical determinant of clinical outcome in PAH. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|