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Homozygous C1qa Deficiency Alters Pulmonary Clearance of Apoptotic Cells* FREE TO VIEW

R. William Vandiver, MD; M. Botto, MD; P. L. Taylor; C. A. Ogden; V. A. Fadok; M. J. Walport; P. M. Henson, PhD
Chest. 2001;120(1_suppl):S25-S26. doi:10.1378/chest.120.1_suppl.S25
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Clearance of dying (apoptotic) cells from inflamed tissues is an integral step in the control of inflammation, and defective processing of autoantigens present in apoptotic cells may contribute to the initiation of autoimmune syndromes. The complement system is one mechanism that has been implicated in apoptotic cell removal. C1q, the first component of the classical complement cascade, binds to apoptotic cells, potentially facilitating their removal by phagocytes. In support of this hypothesis, mice homozygous for C1qa deficiency (C1qa−/−) spontaneously accumulate apoptotic cells in the kidney, and do not effectively clear apoptotic cells during thioglycolate-induced peritonitis. Interestingly, humans homozygous for C1qa−/− develop an early and severe form of systemic lupus erythematosus. We sought to determine whether C1qa−/− delayed resolution of pulmonary inflammation through defective removal of apoptotic cells. Baseline differences between C1qa−/− mice and control mice were assessed by CBCs, BAL WBC subsets, and apoptotic cells. Inflammation in C1qa−/− mice was evaluated in BAL by measurement of WBC subsets at 24, 48, and 72 h posttreatment with 20 μg of intratracheal endotoxin lipopolysaccharide [LPS]. Spontaneous clearance of apoptotic cells in BAL was assessed at these same time points by nuclear morphology, terminal deoxynucleotidyl nick-end labeling, and propidium iodide/annexin V staining. LPS-treated, C1qa−/− mice were also challenged intratracheally with apoptotic human polymorphonuclear leukocytes (PMNs) at 72 h, and clearance was ascertained. No differences were found in baseline blood cell counts, BAL WBC subsets, or BAL apoptotic cells in C1qa−/− mice vs control mice. LPS increased pulmonary PMN, but not macrophage, influx at 48 h and 72 h in C1qa−/− mice compared to control mice. BAL from LPS-challenged C1qa−/− mice and control mice contained only small percentages of spontaneous apoptotic cells (1 to 3%), and no differences were observed between groups. However, when C1qa−/− mice were challenged intratracheally with apoptotic human PMNs, clearance was decreased. These results demonstrate that C1qa−/− impairs clearance of apoptotic cells and enhances pulmonary inflammation. The impact of dysregulated apoptotic cell removal on interstitial lung disease is as yet unknown, but may provide a basis for ongoing inflammation.EST

Abbreviations: C1qa −/− = C1qa deficiency; LPS = lipopolysaccharide; PMN = polymorphonuclear leukocyte




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