Expression of Airway Remodeling Proteins in Mast Cell Activated by TGF-β Released in OVA-Induced Allergic Responses and Their Inhibition by Low-Dose Irradiation or 8-oxo-dG

Abstract

Allergic asthma is characterized by chronic airway remodeling, which is associated with the expression of extracellular matrix proteins (ECM) by TGF-β. However, to date there are no reports demonstrating that structural proteins are directly expressed in mast cells. This study aimed to investigate whether ECM proteins are expressed in mast cells activated with antigen/antibody reaction, and whether the resolution effects of irradiation or 8-oxo-dG may contribute to allergic asthma prevention. Bone marrow-derived mast cells (BMMCs) were activated with DNP-HSA/anti-DNP IgE antibody (act-BMMCs). C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) to induce allergic asthma. Mice were treated orally with 8-oxo-dG or exposed to whole body irradiation (using (137)Cs gamma ray at a dose of 0.5 Gy) for three consecutive days 24 h after OVA challenge. Expression of extracellular matrix (ECM) proteins, TGF-β signaling molecules and NF-κB/AP-1 was determined in the BMMCs, bronchoalveolar lavage (BAL) cells or lung tissues using Western blot, polymerase chain reaction (PCR) and electrophoretic mobility shift assay (EMSA), respectively. Act-BMMCs increased expression of ECM proteins, TGF-β/TGF-β receptor I, TGF-β signaling molecules and cytokines; and increased both NF-κB and AP-1 activity. In addition, the population of mast cells; expression of mast cell markers, TGF-β signaling molecules, ECM proteins/amounts; OVA-specific serum IgE level; numbers of goblet cells; airway hyperresponsiveness; cytokines/chemokines were increased in BAL cells and lung tissues of OVA-challenged mice. All of the above end points were reduced by irradiation or 8-oxo-dG in vitro and in vivo, respectively. The data suggest that mast cells induce expression of ECM proteins through TGF-β produced in inflammatory cells of OVA mice and that post treatment of irradiation or 8-oxo-dG after OVA-challenge may reduce airway remodeling through down-regulating mast cell re-activation by TGF-β/Smad signals.

Continuous Exposure to Low-Dose-Rate Gamma Irradiation Reduces Airway Inflammation in Ovalbumin-Induced Asthma

“…These results indicate that low-dose irradiation does not aggravate asthmatic responses, but attenuates these effects. A previous study has demonstrated that fractionated irradiation at 5 Gy aggravated the severity of asthma [ 10 ], while it was attenuated by 2 Gy irradiation [ 13 , 14 ]. The difference between these previous reports and the present findings could be due to the differences in the dosage and dose rate of irradiation.…”

“…Various studies have demonstrated the relationship between radiation exposure and the development of asthma [ 10 – 12 ], but the results have been contradictory. While one study reported that radiation exposure induced chronic airway inflammation, another study demonstrated that the asthmatic response was attenuated by radiation [ 13 , 14 ]. These conflicting results have been attributed to the radiation dose and rate used.…”

Organ-Specific Effects of Low Dose Radiation Exposure: A Comprehensive Review

“…Although many studies opposed it through showing LDR (0.1 and 0.2 Gy) reportedly promoted cell death, inflammation, ROS generation (lipid oxidation), and DNA damage (5-hydroxymethylcytosine); and activated damage responses (p53, p38, p21, ERK1/2, NF-κB, TGF-β, etc.) in the lung, these studies unanimously agreed that certain irradiation conditions resulted in less severe changes in lung than that in the liver and the spleen ( Sypin et al, 2003 ; Avti et al, 2005 ; Lee et al, 2006 ; Kim et al, 2007 , 2015 ; Hong et al, 2014 ; Jangiam et al, 2018 ). Moreover, the protective roles of LDR in the lung have been demonstrated in various stress models.…”

Reg3g Promotes Pancreatic Carcinogenesis in a Murine Model of Chronic Pancreatitis

“…TGFb is one of a family of multifunctional peptides that regulate proliferation, differentiation, migration, and other functions in tumor immunology. In prostate OVA-expressing transgenic mice, TGFb-mediated repression of T cell function contributed to tumor immunity escapes [45]. Jayaraman et al [46] showed that inhibition of TGFb production boosted tumor-infiltrating CD8 ?…”