According to numerous animal studies, adverse environmental stimuli, including physical, chemical, and biological factors, can cause low-grade chronic inflammation and subsequent tumor development. Human epidemiological evidence has confirmed the close relationship between chronic inflammation and tumorigenesis. However, the mechanisms driving the development of persistent inflammation toward tumorigenesis remain unclear. In this study, we assess the potential role of reactive oxygen species (ROS) and associated mechanisms in modulating inflammation-induced tumorigenesis. Recent reports have emphasized the cross-talk between oxidative stress and inflammation in many pathological processes. Exposure to carcinogenic environmental hazards may lead to oxidative damage, which further stimulates the infiltration of various types of inflammatory cells. In turn, increased cytokine and chemokine release from inflammatory cells promotes ROS production in chronic lesions, even in the absence of hazardous stimuli. Moreover, ROS not only cause DNA damage but also participate in cell proliferation, differentiation, and apoptosis by modulating several transcription factors and signaling pathways. We summarize how changes in the redox state can trigger the development of chronic inflammatory lesions into tumors. Generally, cancer cells require an appropriate inflammatory microenvironment to support their growth, spread, and metastasis, and ROS may provide the necessary catalyst for inflammation-driven cancer. In conclusion, ROS bridge the gap between chronic inflammation and tumor development; therefore, targeting ROS and inflammation represents a new avenue for the prevention and treatment of cancer.

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Phosgene, a highly dangerous chemical warfare agent, is widely used as an industrial chemical. Phosgene inhalation causes acute lung injury (ALI), which may further progress into pulmonary edema. Currently, there is no known antidote for phosgene poisoning. Alpha-1 antitrypsin (α1-AT) is a protease inhibitor that has been used to treat emphysema patients, who are deficient in α1-AT, for decades. Recent studies have shown that α1-AT has both anti-inflammatory and anti-SARS-CoV-2 effects. In this study, we aimed to investigate the role of α1-AT in phosgene-induced ALI. We observed a time-dependent increase in α1-AT expression and secretion in the lungs of rats exposed to phosgene. Interestingly, α1-AT was derived from neutrophils, but not from macrophages or alveolar type II cells, and α1-AT knockdown aggravated phosgene- and lipopolysaccharide (LPS)-induced inflammation and cell death in human bronchial epithelial cells (BEAS-2B). Conversely, α1-AT administration suppressed the inflammatory response and prevented death in LPS- and phosgene-exposed BEAS-2B cells. Furthermore, α1-AT treatment increased the expression of the inhibitor of DNA binding (ID1) gene, which suppressed NF-κB pathway activation, reduced inflammation, and inhibited cell death. These data demonstrate that neutrophil-derived α1-AT protects against phosgene-induced ALI by activating the ID1-dependent anti-inflammatory response. This study may provide novel strategies for the treatment of patients with phosgene-induced ALI.