Haani Tai

Introduction. Smoking-related emphysema induces a disruption to many cellular signaling pathways especially related to inflammation. With inhibition of Phosphoinositide 3-kinase δ (PI3Kδ) showing promising results for reducing inflammation as well as agonizing peroxisome proliferator-activated receptor γ (PPARγ) to induce an anti-inflammatory response and prevent a proinflammatory response.¹ Methods. Two separate mice strains were bred, Cd11c-Cre Ppargflox/flox and doxycycline-treated CCSP-rtTA/(tetO)7-CMV-dnPPARγ, which both demonstrated the effects of absent PPARγ activity.^2,3 In the former strain of mice, ciglitazone, a PPARγ agonist, was administered to combat the effects of emphysema. Additionally, there were trials done to see the effects of different drug compounds used to inhibit PI3Kδ, a pro-inflammatory compound.² Results. The Cd11c mice model spontaneously developed emphysema and lung inflammation that resembled the same phenotype as mice that were exposed to smoke had.²  This was partly due to the loss of suppression of pro-inflammatory molecules such as AP-1, Stat1, Stat3, and NFκB.³ Upon further study there was even a negative correlation discovered between the expression of PPARγ and the severity of emphysema using FEV1 as a metric.² Additionally, In the early stages of doxycycline treatment of the dnPPARγ mice, dnPPARγ was overexpressed resulting in a significant increase in pro-inflammatory molecules such as IL-1β, IL-6, TNF-ɑ, and broncheoalveolar lavage fluid (BALF) concentrations. In the Cd11c mice strain, administration of ciglitazone on human lung myeloid dendritic cells resulted in decreased differentiation of Th1 and Th17 in vitro, and it also reduced the ability of APCs in mice that were exposed to smoke to express IL-17 and IFNγ in Tcells causing an anti-inflammatory response.² There have been two compounds identified, GSK2269557 (compound 2) and GSK2292767 (compound 3), which have shown promising results as specific inhibitors of PI3Kδ. When trying to identify the proper compound, three parameters were examined, high selectivity for the delta isoform, high potency, and high intrinsic clearance and low bioavailability.⁵  Conclusions. Emphysema in patients with COPD is a result of inflammation. While there are many molecules, signals, pathways, and circumstances that relate to anti/pro-inflammatory reactions, the two that were focused on were PI3Kδ and PPARγ.¹ Going forward, there may be viable treatment method found by a dual administration of a PI3Kδ inhibitor and a PPARγ agonist in a dosage that would allow the cells to return to homeostasis.

1. Lin CR, Bahmed K, Kosmider B. Dysregulated Cell Signaling in Pulmonary Emphysema. Front Med (Lausanne). 2022;8:762878. Published 2022 Jan doi:10.3389/fmed.2021.762878
2. Shan M, You R, Yuan X, et al. Agonistic induction of PPARγ reverses cigarette smoke-induced emphysema. J Clin Invest. 2014;124(3):1371-1381. doi:10.1172/JCI70587
3. Wu L, Wang G, Qu P, Yan C, Du H. Overexpression of dominant negative peroxisome proliferator-activated receptor-γ (PPARγ) in alveolar type II epithelial cells causes inflammation and T-cell suppression in the lung. Am J Pathol. 2011;178(5):2191-2204. doi:10.1016/j.ajpath.2011.01.046
4. Ruvuna L, Sood A. Epidemiology of Chronic Obstructive Pulmonary ScienceDirect. 2020;41(3). doi:10.1016/j.ccm.2020.05.002.
5. Kenneth Down, Augustin Amour, Ian R. Baldwin, et al. Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide
6. 3-Kinase δ for the Treatment of Respiratory Disease. Journal of Medicinal Chemistry 2015 58 (18), 7381-7399. DOI: 10.1021/acs.jmedchem.5b00767