Effects of Doxycycline on Production of Growth Factors and Matrix Metalloproteinases in Pulmonary Fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis and a poor prognosis. Alveolar epithelial cells (AECs) are considered to play important roles by releasing growth factors and matrix metalloproteinases (MMPs) and by being involved in epithelial mesenchymal transition in IPF. Doxycycline hydrochloride (DOXY), an inhibitor of MMPs, attenuates pulmonary fibrosis in models and in patients with IPF; however, the mechanism of this action remains obscure. Objectives: The present study investigated the effect of DOXY on growth factors and MMP production in AECs. Methods: Bleomycin (BL)-induced murine pulmonary fibrosis was treated with DOXY and examined by pathological and immunohistochemical staining. The human alveolar epithelial cell line A549 was stimulated with transforming growth factor (TGF)-β1 and incubated with DOXY, and then the expression of growth factors, MMPs, and collagen type I was evaluated at the mRNA and protein levels. We also evaluated the effects of DOXY on the TGF-β1-induced Smad signaling pathway. Results: DOXY reduced fibrosis scores and the production of collagen type I, connective tissue growth factor (CTGF), and TGF-β1 in BL models. DOXY inhibited the mRNA expression of MMP-2, MPP-9, CTGF, and collagen type I as well as the production of MMP-2 and platelet-derived growth factor-AA protein induced in A549 cells by TGF-β1 but not by Smad2 and Smad3 phosphorylation. We did not find a similar effect of DOXY in normal lung fibroblasts. Conclusions: Our results suggest that DOXY could be useful for attenuating pulmonary fibrosis through the inhibition of growth factors and MMP production in AECs.

Doxycycline attenuates paraquat-induced pulmonary fibrosis by downregulating the TGF-β signaling pathway

“…Doxy can suppress the TNF-α pathway to decrease inflammation and improve the antioxidant capacity of cells, ultimately alleviating PF. These results indicate that Doxy can potentially attenuate PF and are consistent with previously reported data (16,17).…”

“…Thus, TGF-β1 is considered a "master switch" of the fibrosis process (26). Previous studies showed that Doxy did not reduce TGF-β-induced Smad phosphorylation and acted via a non-Smad pathway (16). In this study, we show that Doxy inhibits both the Smad-mediated and non-Smad mediated pathways of the TGF-β signaling pathway.…”

“…In addition, the following functions have been reported for Doxy: MMP inhibition, anti-inflammatory properties, and anti-invasive, antiproliferative, anti-angiogenic, and pro-apoptotic functions (13)(14)(15). Recent studies demonstrated that Doxy attenuates bleomycin-induced PF by decreasing inflammation and inhibiting both growth factors and MMPs (16,17). In this study, we report the potential of using Doxy to treat PQinduced PF and describe the role of Doxy in regulating EMT and TGF-β1.…”

Long-term macrolides in diffuse interstitial lung diseases

“…Given these assumptions about the role of bacterial burden and different species in host response and IPF progression, the next step will be to investigate the role played by antibiotic molecules administered for long periods on the natural history of the disease [32][33][34][35][36]. A few studies have explored the role of doxycycline and co-trimoxazole in IPF.…”

The role of a7 nicotine acetylcholine receptors in lung injury and repair.

“…Unfortunately, this information has not yet translated into the development of effective therapeutic strategies, although tetracyclines provide an opportunity with doxycycline inhibiting MMP activity and reducing bleomycin-induced injury in mice [40]. Here, we explore another mechanism of action -the induction of lung tissue remodeling through stimulation of extracellular matrix deposition.…”