Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice

We have investigated a potential role for tumor necrosis factor (TNF)-alpha and its two receptors (p55 and p75) in lung injury. We used several variet ies of mice exposed endotracheally to two fibrogenic agents, silica (0.2 g/ kg) and bleomycin (4 U/kg). The lungs were analyzed at 14 and 28 d after ex posure to bleomycin or silica, respectively, for TNF and TNF receptor (TNFR ) messenger RNA (mRNA), hydroxyproline content, and histopathology. Silica induced increased lover saline-treated animals) expression of TNF mRNA in d ouble TNFR knockout (Ko), C57BL16, BALB/c, and 129/J mice. In contrast, ble omycin increased expression in all but BALB/c mice, which are resistant to the fibrogenic effects of this drug. mRNA expression of both receptors was constitutively expressed in all of the normal murine strains. Silica upregu lated expression of the p75 receptor, but not the p55 receptor, in the C57B L/6, BALB/c, and 129/J mice. In comparison, bleomycin had little effect on either receptor in the bleomycin-resistant BALB/c mice. Hydroxyproline cont ent of the lungs after treatment followed this same pattern, with significa nt increases caused by silica in the C57BL/6, BALB/c, and 129/J mice, where as bleomycin caused no apparent increases in the BALB/c mice. Even though s ilica and bleomycin induced increases in TNF in the TNFR Ko mice, the mice were protected from the fibrogenic effects of these agents. This study supp orts the concept that TNF is a central mediator of interstitial pulmonary f ibrosis.