C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury.
The collectin proteins are innate immune molecules found in high concentrations on the epithelial and endothelial surfaces of the lung. While these proteins are known to have important anti-inflammatory actions in the airways of the lung little is known of their functional importance in the pulmonary circulation. We recently demonstrated that the circulating collectin protein adiponectin has potent anti-inflammatory effects on the lung endothelium, leading us to reason that other structurally related proteins might have similar effects. To test this hypothesis, we investigated the anti-inflammatory actions of C1q in lung endothelial homeostasis and the pulmonary vascular response to LPS or HCl injury. We show that lung endothelium from C1q-deficient (C1q(-/-)) mice expresses higher baseline levels of the vascular adhesion markers ICAM-1, VCAM-1, and E-selectin when compared with wild-type mice. Further, we demonstrate that these changes are associated with enhanced susceptibility of the lung to injury as evident by increased expression of adhesion markers, enhanced production of pro-inflammatory cytokines, and augmented neutrophil recruitment. Additionally, we found that C1q(-/-) mice also exhibited enhanced endothelial barrier dysfunction after injury as manifested by decreased expression of junctional adherens proteins and enhanced vascular leakage. Mechanistically, C1q appears to mediate its effects by inhibiting phosphorylation of p38 mitogen-activated protein kinase (MAPK) and blocking nuclear translocation of the P65 subunit of nuclear factor (NF)-κB. In summary, our findings indicate a previously unrecognized role for C1q in pulmonary vascular homeostasis and provide added support for the hypothesis that circulating collectin proteins have protective effects on the lung endothelium.
From the Center for Translational Medicine and Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Dilip
D
Shah
From the Center for Translational Medicine and Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Freddy
F
Romero
From the Center for Translational Medicine and Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China, and.
Ying
Y
Zhu
From the Center for Translational Medicine and Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Michelle
M
Duong
From the Center for Translational Medicine and Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Jianxin
J
Sun
Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118.
Kenneth
K
Walsh
From the Center for Translational Medicine and Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, Ross.Summer@jefferson.edu.
Ross
R
Summer
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002448:Cell Adhesion; D037222:Collectins / Q000378:metabolism; D015922:Complement C1q / Q000172:deficiency* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism*; D005260:Female; D006706:Homeostasis; D007249:Inflammation / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D055370:Lung Injury / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
D037222:Collectins; D016207:Cytokines; D034741:RNA, Small Interfering; D015922:Complement C1q
collectin; endothelial dysfunction; inflammation; lung injury; neutrophil