The respiratory tract encounters foreign intruders at all times, such as allergy-causing airborne particles, toxic chemical agents, environmental pollutants, and harmful microorganisms (bacteria and viruses).1 A functional respiratory system is crucial in maintaining the health of an individual, while a compromised state within the respiratory tract would lead to serious conditions and disease progression. Lung injury can be classified as acute or chronic. Acute respiratory distress syndrome (ARDS), as an advanced stage of acute lung injury, is noncardiogenic pulmonary oedema that manifests as rapidly progressive dyspnea, tachypnea, and hypoxemia,2 which could be fatal if not properly treated in time. On the other hand, chronic obstructive pulmonary disease (COPD) is a common respiratory condition characterised by persistent airflow limitation. It is progressive and not fully reversible, primarily caused by long-term exposure to air pollution and cigarette smoking, leading to chronic bronchitis and emphysema.3 Cadmium (Cd) is a toxic heavy metal widely exploited in various industries, such as for the production of electronic circuits, Cd paints, Ni-Cd batteries, and Cd quantum dot displays, and is inevitably present in tobacco products.4 Despite the substitution of Cd in Ni-Cd batteries and Cd quantum dot displays with other less toxic/environmental friendly elements, yet, the global use of Cd is still in big demand, and the improper handling/disposal of all these Cd-containing products would eventually pollute our living environment. Once inside the human body, Cd accumulates in multiple organs, and the biological half-time can reach decades.5 In general, occupational Cd exposure can sometimes lead to acute poisoning. In one case, back in 1999, a very typical example of acute Cd inhalation leading to ARDS was documented. A 43-year-old welder developed ARDS after exposure to metal fumes, which contain an elevated air level of Cd.6 In another case, a nonsmoking silversmith after smelting silver adulterated with a large amount of Cd, had a heart rate of 120 beats/min, blood pressure of 150/80, respiratory rate of 48–52/min, PaO2/FiO2 ratio of 100, and central cyanosis, and was diagnosed with ARDS.7 The above examples provided strong evidence of Cd inhalation in the development of ARDS in humans. On the other hand, the general public is chronically exposed to Cd on a daily basis from Cd-contaminated air (from industrial fume emission, first-hand and/or second-hand cigarette smoke), and after a certain period of time, this would likely predispose humans to various lung-related diseases. Besides induction of pro-inflammatory cytokines,8 Cd has been shown to promote various forms of cell death, depending on the concentration, duration of exposure, and also the exposure scenarios, that is, whether in in vitro or in vivo conditions. In the past, many studies have reported that Cd could exert oxidative stress, damaging various cellular components and inducing cell apoptosis or necrosis.9 Lately, other types of cell death induced by Cd exposure were reported, including ferroptosis (a non-apoptotic cell death mechanism characterised by iron-dependent membrane lipid peroxidation)10 and even pyroptosis (a highly inflammatory form of cell death in which mtDNA leakage into the cytoplasm and activated the cGAS-STING pathway). Inhibition of the cGAS-STING pathway significantly alleviated lung injury by Cd exposure in mice.11 All these various forms of cell death can be generally explained by the dosage of Cd being exposed and also the cellular sensitivity to Cd in different cell types. In some earlier studies, using rats as a model, addressed the effect of maternal Cd exposure in vivo, which demonstrated that maternal Cd exposure could impact the maturation of the foetal pulmonary surfactant system and induce respiratory distress syndrome.12, 13 However, whether the same phenomenon would occur in humans is uncertain, and therefore, research on ARDS and Cd exposure using human lung organoids is vital and urgently needed. In conclusion, although some case studies and animal experiments have connected the role of Cd to lung injury, there are still many unanswered questions to be tackled. For example, which lung cell subtypes, immune cell subtypes, and subcellular organelles are more relevant to Cd-induced acute lung injury/ARDS? Also, are there differences in Cd uptake and metabolism among all these cell subtypes? Interestingly, our recent finding of Cd-binding proteins using Cd-immobilised metal ion affinity chromatography (Cd-IMAC) has identified nucleophosmin (NPM1) as a strong Cd-binding protein that is localised inside the nucleolus in normal situations. Cd exposure induced NPM1 remodelling from the nucleolus to nucleoplasm, resulting in nucleolar stress and compromised rRNA biogenesis in human bronchial epithelial BEAS-2B cells.14 It would be tempting to examine further whether NPM1 and other unidentified Cd-binding proteins, as well as the organelles that could be involved in Cd-induced lung injury in vivo. We believe that with the use of single-cell and spatiotemporal analyses, this shall provide novel insights and thus more effective ways can be employed in treating/preventing Cd-related lung injuries. Andy T. Y. Lau and Yan-Ming Xu wrote this article. We would like to thank Professor Xiangdong Wang for the advice and critical suggestions on the preliminary planning of this work. None.
Xu et al. (Tue,) studied this question.