Why new biology must be uncovered to advance therapeutic strategies for chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by the destruction of alveolar tissue (in emphysema) and airway remodeling (leading to chronic bronchitis), which cause difficulties in breathing. It is a growing public health concern with few therapeutic options that can reverse disease progression or mortality. This is in part because current treatments mainly focus on ameliorating symptoms induced by inflammatory pathways as opposed to curing disease. Hence, emerging research focused on upstream pathways are likely to be beneficial in the development of efficient therapeutics to address the root causes of disease. Some of these pathways include mitochondrial function, cytoskeletal structure and maintenance, and airway hydration, which are all affected by toxins that contribute to COPD. Because of the complexity of COPD and unknown targets for disease onset, simpler model organisms have proved to be useful tools in identifying disease-relevant pathways and targets. This review summarizes COPD pathology, current treatments, and therapeutic discovery research, with a focus on the aforementioned pathways that can advance the therapeutic landscape of COPD.

Keywords: airway and alveolar epithelium; cigarette smoke; cytoskeleton; mitochondria; model organisms.

Figure 1.

The chronic obstructive pulmonary disease (COPD) pipeline focuses on targeting inducers of inflammation. Cigarette smoke activates numerous downstream pathways and targets that lead to inflammation, including inflammatory mediators, oxidative stress, kinases, and phosphodiesterases. Current therapeutic strategies aim to reduce inflammatory responses by inhibiting specific targets under each major group.

Figure 2.

Emerging chronic obstructive pulmonary disease (COPD) biology offers potentials for new breakthroughs in therapeutic development. The airway epithelium is composed of ciliated cells (blue), secretory cells (orange), and basal cells (green) on top of a basement membrane (BM) and extracellular matrix (ECM). Its role is to act as a barrier to toxins that enter the airway, including cigarette smoke. Continual exposure to cigarette smoke in the epithelium, however, can contribute to COPD phenotypes. Pathways that are affected by cigarette smoke upstream of inflammatory responses are currently being researched and may be helpful in identifying new targets for drug development. These pathways include airway hydration, the structural integrity of the airway epithelium and its barrier function, mitochondrial dysfunction and mitochondrial reactive oxygen species (ROS) production, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT).

Figure 3.

Various model organisms can be utilized to identify new and relevant biology in chronic obstructive pulmonary disease (COPD). Mice have been heavily used to study COPD and understand disease progression, but the processes that come with identifying new essential disease biology are more complex in both human and mouse. Interestingly, there is emerging research on finding additional disease-relevant biology with simpler model organisms. New pathways affected by cigarette smoke have been identified in in vitro cell culture models, Caenorhabditis elegans (23), Drosophila (47), and social amoeba Dictyostelium discoideum (32). By utilizing these simpler models, there is the potential to recapitulate major findings or discover novel research on COPD, which can then be further studied in complex systems such as human and mouse.