Inhibition of Sephadex-induced lung injury in the rat by Ro 45-2081, a tumor necrosis factor receptor fusion protein.

Abstract

Tumor necrosis factor (TNF) is an inflammatory cytokine produced by many cell types which may contribute to the pathophysiology of a variety of lung diseases. In this study we have used Ro 45-2081 (a soluble receptor composed of the human p55 TNF receptor and human heavy-chain immunoglobulin G) to explore the role of TNF in the acute inflammatory response in the rat lung to intravenous injection of Sephadex beads. The effects of Ro 45-2081 have also been compared with those of dexamethasone. At 24 and 72 h after Sephadex, there was a significant increase in the total number of leukocytes in bronchoalveolar lavage fluid (BALF). At 24 h, the number of neutrophils comprised around 50% of the total leukocyte number, decreasing to around 10% of total by 72 h. The eosinophil count was maintained at around 10% of the total leukocyte number. Pretreatment with either Ro 45-2081 [1 and 3 mg kg-1, intraperitoneally (i.p.)] or dexamethasone (0.1 and 0.3 mg kg-1, i.p.) inhibited the neutrophilia at 24 h after Sephadex, although Ro 45-2081 had no significant effect on total cell number. At 72 h after Sephadex, Ro 45-2081 (1 and 3 mg kg-1, i.p., daily) significantly reduced the neutrophil influx into BALF but had no inhibitory effect on eosinophil number. In contrast, dexamethasone (0.1 and 0.3 mg kg-1, i.p., daily) virtually abolished the infiltration of neutrophils and eosinophils into BALF. The lack of effect of Ro 45-2081 on eosinophil infiltration into the rat lung and the inhibition caused by dexamethasone suggest that factors other than TNF are involved in this part of the inflammatory response induced by Sephadex. However, the inhibitory effects of Ro 45-2081 show that TNF may play an important role in the recruitment of neutrophils into the lungs of Sephadex-treated rats.

Effects of uridine, isomatitol and 4-thiouridine on in vitro cell adhesion and in vivo effects of 4-thiouridine in a lung inflammation model

“…It is difficult to determine whether the decrease in TNFa is due to a direct inhibitory effect on TNF production or an indirect effect reflecting decreased activation as a result of reduced cell influx. Considering the roles TNFa plays in inflammation, including activation of several inflammatory cell types, acting as a chemoattractant and promoting increases in AHR, the observed reduction in TNF levels is important irrespective of the mechanism [21,24].…”

Tumour necrosis factor‐α expression and cell recruitment in Sephadex particle‐induced lung inflammation: effects of dexamethasone and cyclosporin A

“…These results are consistent with induction of TNF‐ α being an important early event in the induction of lung inflammation. Although it is known that TNF‐ α possesses diverse pro‐inflammatory properties (see Introduction and reviews by Kips et al , 1993; and Shah et al , 1995) and blockade of the actions of TNF‐ α abrogates granulocyte mobilization into lung (Gater et al , 1996; Renzetti et al , 1996), this is the first description of induction of TNF‐ α expression in lung tissue following an inflammatory stimulus. These observations raise the question as to whether TNF‐ α expression simply reflects mononuclear cell numbers or whether the cytokine has an active role to play in chemotaxis of these cells.…”

“…TNF‐ α is elevated in sputum of patients with acute attacks of asthma and TNF‐ α levels are up to 20 times higher in bronchoalveolar fluid from symptomatic compared to asymptomatic asthma patients (Ying et al , 1991). Furthermore, blocking of TNF‐ α activity in vivo with a TNF receptor fusion protein inhibits influx of granulocytes into BAL fluid in animal models of lung inflammation (Renzetti et al , 1996; Gater et al , 1996).…”

“…Furthermore it is not known how lung TNF‐ α expression may be controlled pharmacologically, nor whether inhibition of TNF‐ α expression might influence inflammatory changes in lung, particularly cell recruitment. To answer these questions we have utilized the rat model of Sephadex‐induced lung inflammation, in which particles become lodged in the capillaries of the lung and the resulting trauma leads to cell infiltration and airway hyperresponsiveness (Laycock et al , 1986; Cook, 1990; Spicer et al , 1990; Asano et al , 1992; Gater et al , 1996). We have studied the sequence of migration of neutrophils, eosinophils and mononuclear cells into the lung in this model, its relation to expression of TNF‐ α mRNA, and the pharmacological control of these processes.…”

Production of Granulomatous Inflammation in Lungs of Rat Pups and Adults by Sephadex Beads

“…Pretreatment with a TNF receptor fusion protein (Ro 45-2081) significantly inhibited infiltration of eosinophils and neutrophils into the BALF after antigen challenge in sensitized rats (28), indicating a requirement for TNF-␣ in accumulation of eosinophils and neutrophils. However, the same dose of Ro 45-2081 used in the study (28) reduced only neutrophilic infiltration into the BALF in Sephadex-treated rats (29). Thus, TNF-␣ may play a role in neutrophil recruitment into the lungs of Sephadex-treated rats, and the eosinophil response to Sephadex beads may be resistant to TNF blockade.…”