IL-13 immunotoxin accelerates resolution of lung pathological changes triggered by silica particles in mice.

Instillation of silica into the lungs of rodents results in pathological changes that strongly mimic human silicosis, an occupational lung disease marked by restrictive airway obstruction, inflammation, and fibrosis. Because IL-13 is a pivotal proinflammatory and fibrogenic cytokine, we examined whether a recombinant immunotoxin comprised of human IL-13 and a mutated form of Pseudomonas exotoxin (IL-13-PE) might affect pathological features of experimental silicosis. Mice received a single intranasal instillation of silica particles and were treated with intranasal IL-13-PE every other day from days 21 to 27 postsilica. The sensitivity of putative cell targets to IL-13-PE was also assessed in in vitro settings. Upregulation of IL-13, its receptor subunits IL-13Rα1 and IL-13Rα2, and shared receptor IL-4Rα were associated with development of granulomatous lung inflammation triggered by silica. IL-13-PE inhibited silica-induced granuloma and fibrotic responses noted at 24 h and 15 d after the last treatment. Upregulation of TNF-α, TGF-ß, and chemokines, as well as increased collagen deposition and airway hyperreactivity to methacholine were all clearly sensitive to IL-13-PE. In addition, IL-13-PE inhibited both IL-13-induced proliferation of cultured lung fibroblasts from silicotic mice and silica-induced IL-8 generation from A549 cells. In conclusion, our findings show that therapeutic treatment with IL-13-PE can reverse important pathological features caused by inhalation of silica particles, suggesting that this recombinant immunotoxin is a promising molecular template in drug discovery for the treatment of silicosis.

Endothelin ET(B) receptor-mediated mechanisms involved in oleic acid-induced acute lung injury in mice.

The receptors underlying the endothelin-dependent component of lung plasma extravasation and leucocyte infiltration induced by oleic acid were assessed in mice. Oleic acid (1 mg.kg(-1) intravenously), but not endothelin-1 (up to 1 nmol.kg(-1) intravenously), increased accumulation of Evans blue in the lungs (excluding the trachea and main bronchi) from 11.8+/-3.9 to 98.6+/-10.7 microg 1 h after injection. Bosentan, the antagonist of endothelin receptors (ET(A) and ET(B)) or the selective ET(B) receptor antagonists Ro 46-8443 or A-192621 (administered 1 h before oleic acid at doses of 30, 10 and 30 mg x kg(-1) respectively) reduced the effect of oleic acid by 71%, 58% and 79% respectively. However, the selective ET(A) receptor antagonist A-127722.5 (10 mg x kg(-1)) was inactive. Oleic acid (2 mg xkg(-1), intravenously) raised the number of total leucocytes, mononuclear cells and neutrophils in broncho-alveolar lavage fluid 4 h after injection. Bosentan and Ro 46-8443 (at doses of 30 and 10 mg x kg(-1) respectively) inhibited the neutrophil infiltration induced by oleic acid by approx. 80%. None of the antagonists modified control (basal) pulmonary microvascular permeability or total and differential cell counts. Thus, endogenous endothelins, acting via ET(B) receptor-dependent mechanisms, play a major role in oleic acid-induced lung injury in the mouse by promoting infiltration of circulating neutrophils and enhancement of pulmonary microvascular plasma extravasation. These findings suggest that either ET(B) or mixed ET(A)/ET(B) receptor antagonists might be beneficial in the treatment of the adult respiratory distress syndrome.