Role of Interleukin-6 in Bleomycin-Induced Lung Inflammatory Changes in Mice

Abstract

Interleukin-6 (IL-6) is known to be involved in the pathogenesis of various inflammatory diseases, but its role in bleomycin (BLM)-induced lung injury and subsequent fibrotic changes remains to be determined. We evaluated the role of IL-6 in the lung inflammatory changes induced by BLM using wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice. The mice were treated intratracheally with 1 mg/kg BLM and killed 2, 7, or 21 days later. Lung Inflammation in the acute phase (Days 2 and 7) was assessed by differential cell counts in bronchoalveolar lavage (BAL) fluid and cytokine levels in the lung. Lung fibrotic changes were evaluated on Day 21 by histopathology and collagen assay. On Day 2, BLM administration induced significant increases in the numbers of total cells, macrophages, and neutrophils in BAL fluid, which were attenuated in IL-6(-/-) mice (P < 0.05). Lung pathology also showed inflammatory cell accumulation, which was attenuated in the IL-6(-/-) mice compared with WT mice. In WT mice, elevated levels of TGF-beta(1) and CCL3 were observed 2 and 7 days after BLM challenge, respectively. On Day 7, BLM-induced inflammatory cell accumulation did not differ between the genotypes. Lung pathology 21 days after BLM challenge revealed significant fibrotic changes with increased collagen content, which was attenuated in IL-6(-/-) mice. Although the TGF-beta(1) level in the lung did not differ between the genotypes on Day 21, CCL3 was significantly lower in IL-6(-/-) mice. These results indicate that IL-6 may play an important role in the pathogenesis of BLM-induced lung injury and subsequent fibrotic changes.

Matrilysin (Matrix Metalloproteinase-7) Regulates Anti-Inflammatory and Antifibrotic Pulmonary Dendritic Cells That Express CD103 (αEβ7-Integrin)

“…6 of activation due to the absence of E-cadherin shedding. mRNA levels for TGF-␤1 did not differ between genotypes, but mRNA for connective tissue growth factor and IL-6, which are profibrotic in this model, [45][46][47][48][49] were significantly higher in CD103 Ϫ/Ϫ lung tissues than in wild-type lungs, consistent with the marked increase in pulmonary fibrosis in seen CD103…”

Effects of a leukotriene B4receptor antagonist on bleomycin-induced pulmonary fibrosis

“…High IL-6 levels are correlated with alveolar hypercellularity and neutrophil counts in IPF [28]. Recently, IL-6-deficient mice demonstrated attenuation in bleomycin-induced lung injury and fibrosis [29]. Therefore, one of the mechanisms for the inhibition of inflammation and fibrosis by ONO-4057 may be associated with the decrease in IL-6.…”

Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages

“…Several recent publications have shown that Mfge8-independent apoptotic cell clearance induces phagocyte release of IL-1β and IL-6 (43,44), cytokines that induce inflammation and fibrosis (45,46). Conversely, Mfge8-dependent apoptotic cell clearance has been shown to induce the release of TGF-β, a profibrotic and antiinflammatory cytokine (32,44).…”