## 5 Application as a Disease Model for Vascularized Lower Respiratory-Physiology-On-A-Chip
### Asthma, COPD, and PE  
Asthma is a chronic inflammatory disease of the airways characterized by various forms of airway obstruction, airway hyperresponsiveness, and airway inflammation. The incidence of asthma has increased in recent years, despite the availability of various drugs, and the underlying disease pathogenesis remains unclear. Therefore, it is important to continuously investigate the pathophysiology and pathogenesis of asthma in humans and to develop new drugs based on these findings. [PERSON] et al. (2019) developed a small airway chip for human study that contains perfusable vasculatures comprising bronchial epithelium and vascular endothelial cells. They added interleukin-13 (IL-13), a commonly used experimental asthma inducer to the chip. They investigated the production of cytokines in the presence or absence of vasculatures on the small airway-on-a-chip. As a result, this effect appeared to be specific to the chip with vasculatures compared to the chip without vasculatures, which affected the secretion of RANTES, IL-6, and IL-10 under the presence of the polyinosinic-polyctidylic acid (poly (I: C)) condition. The poly (I: C) triggered inflammatory responses similar to in vivo. In addition, [PERSON] et al. (2017) used 3D bioprinting to mimic the combination of airways with vascular networks in vitro. They developed a vascular platform via 3D printing of cell-containing dECM bioinks and also integrated them with epithelial models. In fact, the differentiation and function of epithelial cells were strongly apparent on the platform with vasculatures, along with the pathophysiological symptoms of asthma induced by IL-13. These results showed a strong increase in the number of goblet cells and reduced cilia cells. Expression of ZO-1, which is indicative of epithelial barrier function, was significantly decreased upon IL-13 treatment, and the transepithelial electrical resistance (TEER) value was also reduced. These results confirmed that the pathological symptoms occurring in the airway epithelium of asthma patients were highly reproduced in the airway platform with vasculatures. COPD is a type of obstructive pulmonary disease with chronic airflow. It is common for the condition to worsen over time. Abnormal inflammatory reactions, such as the inhalation of harmful particles, gases, or smoking, reduce lung function more rapidly than others. Symptoms of COPD include coughing, sputum, and dyspnea during exercise. Chronic bronchitis and emphysema are commonly referred to as COPD because it is fundamentally difficult to distinguish their causes, symptoms, and treatment. [PERSON] et al. (2019) simulated the COPD environment by incubating human tracheal epithelial cells (HTEpC) from COPD patients on the vascularized small airway-on-a-chip. Normal or COPD epithelial cells in the chip were stimulated with LPS and poly (I: C), which increased the secretion of IL-8 and M-CSF on the COPD chips, respectively. This disease model did not show significant changes compared to the healthy model. M-CSF levels were increased only in the small airway-on-a-chip treated with poly (I: C). Their study confirmed that M-CSF may be a new biomarker of COPD exacerbation caused by respiratory virus infection. Small airway-on-a-chip with epithelial cells from patients with COPD reproduce the disease characteristics, such as selective cytokine hypersecretion, increased neutrophil recruitment, and clinical exacerbation by viral and bacterial infections. In general, PE is caused by heart problems, and it is difficult to breathe because of the accumulation of excess lung fluid in numerous air sacs in the lungs. [PERSON] et al. (2018) induced PE in the microfluidic lung-on-a-chip. In these experiments, fluid leaked into the air chamber when interleukin-2 (IL-2) was added to the microvascular channel, and further damage to the lung barrier and a three-fold increased leakage occurred with the periodic mechanical modifications introduced with IL-2.