Abstract
Background. Tumor necrosis factor (TNF)-α is a critical effector of lipopolysaccharide (LPS)-induced acute lung injury, and its effects are mediated by two structurally related receptors, RI and RII. Cellular adhesion molecules and C-X-C chemokines (Keratinocyte chemoattractant (KC) and macrophage inflammatory protein [MIP]-2) regulate tissue neutrophil polymorphonuclear neutrophil (PMN) accumulation in a multitude of inflammatory states. We hypothesized that TNFRI signaling dictates PMN accumulation in the lung via regulation of chemokine molecule production. Therefore, the purposes of this study were to (1) delineate LPS-induced lung TNF-α production and (2) characterize the contribution of both TNF receptors to lung chemokine production and neutrophil influx following systemic LPS. Methods. Wild-type or TNFRI and TNFRII knockout (KO) mice were injected with vehicle (saline) or LPS (Escherichia coli 0.5 mg/kg intraperitoneally). After 2, 4, 6, or 24 h, lungs were analyzed for TNF-α and chemokine (KC and MIP-2) protein expression (enzyme-linked immunosorbent assay) and PMN accumulation (myeloperoxidase assay). Results. There was an increase in total lung TNF-α (vehicle, 5.0 ± 1.2 pg/mg total protein vs LPS, 950 ± 318; P < 0.05) after LPS. Lung chemokine production and PMN accumulation were also increased compared to vehicle-injected mice. Lung chemokine production and PMN accumulation were significantly lower in TNFRI KO, but not TNFRII KO, mice, despite no difference in TNF-α production (TNFRI KO, 925 ± 301 vs TNFRII KO, 837 ± 267, P = 0.82). Conclusions. Acute lung injury following systemic LPS administration is characterized by increased lung (1) TNF-α production, (2) C-X-C chemokine production, and (3) neutrophil accumulation. The maximal effect of LPS-induced lung neutrophil accumulation appears to be dependent upon the TNFRI receptor but not the TNFRII receptor.
Original language | English (US) |
---|---|
Pages (from-to) | 232-237 |
Number of pages | 6 |
Journal | Journal of Surgical Research |
Volume | 101 |
Issue number | 2 |
DOIs | |
State | Published - 2001 |
Keywords
- Injury
- KC
- Knockout mouse
- MIP-2
- Sepsis
- TNF receptor II
- p55
- p75
ASJC Scopus subject areas
- Surgery