LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling

Abstract

Radiation therapy is an important modality in the treatment of lung cancer, but it can lead to radiation pneumonitis, and eventually radiation fibrosis. To date, only few available drugs can effectively manage radiation-induced pulmonary fibrosis. Lipoxins are endogenous molecules exhibit anti-inflammatory and pro-resolving effects. These molecules play a vital role in reducing excessive tissue injury and chronic inflammation; however, their effects on radiation-induced lung injury (RILI) are unknown. In this study, we investigated the effects of lipoxin A 4 (LXA 4) on RILI using our specialized small-animal model of RILI following focal-ablative lung irradiation (IR). LXA 4 significantly inhibited immune-cell recruitment and reduced IR-induced expression of pro-inflammatory cytokines and fibrotic proteins in the lung lesion sites. In addition, micro-CT revealed that LXA 4 reduced IR-induced increases in lung consolidation volume. The flexiVent TM assays showed that LXA4 significantly reversed IR-induced lung function damage. Moreover, LXA4 downregulated the activities of NF-κB and the Smad-binding element promoters. The expression of FPR2, an LXA 4 receptor, increased during the development of IR-induced pulmonary fibrosis, whereas silencing of endogenous LXA 4 using an antagonist (WRW4) or FPR2 siRNA resulted in impaired development of pulmonary fibrosis in response to IR. Collectively, these data suggest that LXA 4 could serve as a potent therapeutic agent for alleviating RILI.

Could Arachidonic Acid-Derived Pro-Resolving Mediators Be a New Therapeutic Strategy for Asthma Therapy?

“…Due to the possible therapeutic application of LXA 4 , some clinical trials using this LX, its analogues, or LXA 4 receptor agonist BML-111 were administered in asthmatic patients. The nebulization of LXA 4 reduced LTC4-induced bronchoconstriction ( 67 ); however, the rapid inactivation and significant instability to exposure to light and acids of LXA 4 ( 117 ) make its clinical use difficult. Furthermore, the inhalation of LXA 4 analog or BML-111, which is more potent and stable than LXA 4 itself ( 118 ), improved the lung function ( 68 ) ( Table 1 ).…”

SPM Receptor Expression and Localization in Irradiated Salivary Glands

“…For instance, activation of this receptor with LXA 4 suppressed immune cell recruitment and downregulated TGFβ1, thereby leading to reduced fibrosis and improved function in an irradiated lung mouse model. 47 Moreover, activation of ALX/FPR2 with a synthetic agonist reduced both collagen density and hydroxyproline levels in a scleroderma mouse model, thus indicating reduced fibrosis. 48 Given that ALX/FPR2 is expressed in healthy mucous acini and intercalated duct cells within hSMGs and is likewise maintained after RT, agonists for this receptor could be used to both resolve inflammation and reduce fibrosis in irradiated glands.…”

Promising Biomarkers of Radiation-Induced Lung Injury: A Review

“…TGF-β partly functions in a pro-fibrotic role by binding to the transmembrane proteins of serine/threonine kinase to transduce signals. Multiple signaling cascades, including ERK/GSK3β/Snail, Smad/Snail, and PI3K/AKT/mTOR axis, are activated [ 49 , 50 , 51 ]. It has been demonstrated that TGF-β enhances the expression of Insulin-like growth factor binding protein (IGFBP7), which further activates the ERK signaling pathway to promote EMT of AEC II [ 52 ].…”

“…As the most important pro-fibrotic factor, TGF-β1 promotes the differentiation of fibroblasts into myofibroblasts and the synthesis of ECM proteins [ 51 ]. Its central role in fibrosis progression is summarized in Section 2 .…”