Chinese Herbs and Repurposing Old Drugs as Therapeutic Agents in the Regulation of Oxidative Stress and Inflammation in Pulmonary Diseases

Abstract

Several pro-inflammatory factors and proteins have been characterized that are involved in the pathogenesis of inflammatory diseases, including acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, induced by oxidative stress, cytokines, bacterial toxins, and viruses. Reactive oxygen species (ROS) act as secondary messengers and are products of normal cellular metabolism. Under physiological conditions, ROS protect cells against oxidative stress through the maintenance of cellular redox homeostasis, which is important for proliferation, viability, cell activation, and organ function. However, overproduction of ROS is most frequently due to excessive stimulation of either the mitochondrial electron transport chain and xanthine oxidase or reduced nicotinamide adenine dinucleotide phosphate (NADPH) by pro-inflammatory cytokines, such as interleukin-1β and tumor necrosis factor α. NADPH oxidase activation and ROS overproduction could further induce numerous inflammatory target proteins that are potentially mediated via Nox/ROS-related transcription factors triggered by various intracellular signaling pathways. Thus, oxidative stress is considered important in pulmonary inflammatory processes. Previous studies have demonstrated that redox signals can induce pulmonary inflammatory diseases. Thus, therapeutic strategies directly targeting oxidative stress may be effective for pulmonary inflammatory diseases. Therefore, drugs with anti-inflammatory and anti-oxidative properties may be beneficial to these diseases. Recent studies have suggested that traditional Chinese medicines, statins, and peroxisome proliferation-activated receptor agonists could modulate inflammation-related signaling processes and may be beneficial for pulmonary inflammatory diseases. In particular, several herbal medicines have attracted attention for the management of pulmonary inflammatory diseases. Therefore, we reviewed the pharmacological effects of these drugs to dissect how they induce host defense mechanisms against oxidative injury to combat pulmonary inflammation. Moreover, the cytotoxicity of oxidative stress and apoptotic cell death can be protected via the induction of HO-1 by these drugs. The main objective of this review is to focus on Chinese herbs and old drugs to develop anti-inflammatory drugs able to induce HO-1 expression for the management of pulmonary inflammatory diseases.

Keywords: HO-1; Nrf2; ROS; inflammatory mediators; pulmonary alveolar epithelial cells; tracheal smooth muscle cells.

Figure 1

The roles of ROS, pro-inflammatory mediators, and transcription factors AP-1 and NF-κB in pulmonary inflammatory diseases. Pathogen-activated molecular patterns (PAMPs), including endotoxins (LPS or LTA), growth factors (EGF or PDGF), and cytokines (IL-1β or TNF-α), activate downstream pathways (p38 MAPK, JNK1/2, and ERK1/2) via their respective receptors (TLR, EGFR, DPGFR, IL-1R, and TNFR) to promote transcription factors NF-κB and AP-1 activities also activated by ROS, leading to genes transcription (including cytokines, chemokines, MMP-9, COX-2, iNOS, ICAM-1, VCAM-1, MUC5AC, and MUC5B) and pulmonary inflammation.

Figure 2

The functions of PPARs agonists in pulmonary inflammation. PPARs agonists and PPARs agonist-induced HO-1 upregulation can inhibit NF-κB activity via blocking IKK activity and IκB phosphorylation, leading to suppression of NF-κB nuclear translocation and DNA binding activity and in turn reduction of gene expression including MCP-1, iNOS, VCAM-1, ICAM-1, P-selectin, IL-1, IL-6, TNF-α, COX-2, and RANTEs.

Figure 3

The anti-inflammatory, anti-fibrotic, and anti-apoptotic mechanisms of Chinese herbs in the lungs. Herbs can target individual signal molecules including ROS, MAPKs, and NF-κB as well as pro-inflammatory mediators to block the expression of pro-inflammatory proteins, pro-fibrotic proteins, and pro-apoptotic proteins.