The Effect of Tumour Necrosis Factor (TNF) Inhibitors in Clostridium difficile Toxin‐Induced Paw Oedema and Neutrophil Migration

Abstract

Clostridium difficile produces a potent enterotoxin and a cytotoxin, toxin A and toxin B, respectively. These toxins are associated with pseudomembranous colitis and antibiotic-associated diarrhoea. In the present study, we investigated the oedematogenic activity of both toxins, characterizing the time-course and dose-response of this pro-inflammatory event. We also explored the effects of two inhibitors of tumour necrosis factor (TNF) production, thalidomide and pentoxifylline, in neutrophil recruitment and the oedematogenic activity of these toxins. Subplantar injection of toxin A induced paw oedema with a maximal response at 1 microg, reaching a maximal value 9 hr after toxin A challenge (toxin A 1 microg:1.39+/-0.09 ml). Toxin B also showed a dose-dependent oedematogenic activity with a late peak at 24 hr and a maximal response at a dose of 0.1 microg (toxin B 0.1 microg:1.74+/-0.12 ml). Pentoxifylline, but not thalidomide, significantly reduced the oedema induced by Toxin A (pentoxifylline 135 mg/kg:60% of inhibition) and Toxin B (pentoxifylline 135 mg/kg:33.6% of inhibition). Both thalidomide and pentoxifylline were able to significantly reduce neutrophil influx into the peritoneal cavities of rats evoked with Toxin A (thalidomide 45 mg/kg: 53.1% of inhibition; pentoxifylline 45 mg/kg:47.1% of inhibition) and Toxin B (thalidomide 45 mg/kg:46.8% of inhibition; pentoxifylline 45 mg/kg:63.1% of inhibition). This study demonstrates the oedematogenic activities of both toxins with distinct potencies and time-courses. These data also show an inhibitory effect of pentoxifylline in toxin A and B-induced paw oedema. Furthermore, both pentoxifylline and thalidomide significantly inhibited the Clostridium difficile toxins-induced neutrophil migration.

Experimental murine mycobacteriosis: evaluation of the functional activity of alveolar macrophages in thalidomide- treated mice

“…Thus, even though other investigators have reported the ability of this drug to inhibit leukocyte chemotaxis (27), our results demonstrate that in the present model thalidomide did not show a direct chemotactic effect on the afflux of cells to the pulmonary environment. The effect of thalidomide may be dose dependent in this process since Carneiro-Filho et al (27), using a drug concentration of 45 mg/kg body weight, observed this phenomenon.…”

“…The effect of thalidomide may be dose dependent in this process since Carneiro-Filho et al (27), using a drug concentration of 45 mg/kg body weight, observed this phenomenon. The results obtained with IL-8, a potent chemotactic factor which appears to be dose dependently inhibited by thalidomide, support this premise (28).…”

Thalidomide Reduces Lipopolysaccharide/Zymosan-Induced Acute Lung Injury in Rats

“…Pretreatment of rats with thalidomide significantly decreased pulmonary microvascular permeability, although the W/D lung weight ratio was not significantly reduced when compared with the combined LPS and zymosan group. This finding indicates that thalidomide can inhibit neutrophil recruitment and activation, concurring with a previous report [5]. On the other hand, the lack of attenuation of the W/D lung weight ratio may be explained by two observations.…”

Comparison between Symptomatic and Asymptomatic Mice after Clostridioides difficile Infection Reveals Novel Inflammatory Pathways and Contributing Microbiota

“…The usage of antiinflammatory drugs has been considered a risk factor for developing severe CDI in several studies. These drugs include corticosteroids, NSAIDs (non-steroidal anti-inflammatory drugs, prostaglandin inhibitor), anti-TNF-α monoclonal antibodies (mAbs), and histamine receptor blockers [14][15][16][17][31][32][33][34][35]. Pretreating mice with indomethacin (an NSAID) or anti-TNF-α mAb before infecting with C. difficile resulted in more severe CDI [36][37][38].…”