Innovations in asthma therapy: is there a role for inhaled statins?

Abstract

Asthma manifests as chronic airflow obstruction with persistent inflammation and airway hyperresponsiveness. The immunomodulatory and anti-inflammatory properties of the HMG-CoA reductase (HMGCR) inhibitors (a.k.a. statins), suggest a therapeutic role in chronic inflammatory lung diseases. However, despite positive laboratory investigations and promising epidemiological data, clinical trials using statins for the treatment of asthma have yielded conflicting results. Inadequate statin levels in the airway compartment could explain these findings. Areas covered: HMGCR is in the mevalonate (MA) pathway and MA signaling is fundamental to lung biology and asthma. This article will discuss clinical trials of oral statins in asthma, review lab investigations relevant to the systemic versus inhaled administration of statins, address the advantages and disadvantages of inhaled statins, and answer the question: is there a role for inhaled statins in the treatment of asthma? Expert commentary: If ongoing investigations show that oral administration of statins has no clear clinical benefits, then repurposing statins for delivery via inhalation is a logical next step. Inhalation of statins bypasses first-pass metabolism by the liver, and therefore, allows for delivery of significantly lower doses to the airways at greater potency. Statins could become the next major class of novel inhalers for the treatment of asthma.

Keywords: Asthma; atorvastatin; drug repositioning; drug repurposing; inflammatory lung disease; inhalation; inhaled; inhaler; pravastatin; rosuvastatin; simvastatin; statins.

Figure 1. The mevalonate pathway and statin mechanism

The mevalonate (MA) pathway is a ubiquitous biochemical pathway present in all cells. It is essential for many diverse and basic cellular functions, and is necessary for cell survival. The downstream metabolites of MA include the sterol (e.g. squalene, cholesterol) and isoprenoid (IPP, FPP, GGPP) metabolites. The isoprenoids are essential for the function of the small GTPases Rho, Rab, and Ras families. The statins directly inhibit HMG-CoA reductase which depletes intracellular pools of MA and downstream metabolites important in cell cycle, survival, proliferation, regeneration, signaling, and homeostasis.

Figure 2. Cell types and pathways affected by statins in the lung

The statins have been studied in various cell culture and animal models. They affect diverse mechanisms and cellular processes in both lung immune cells and resident cells [29]. The statins inhibit the influx of inflammatory cells into airway and lung tissues (e.g. neutrophils, eosinophils, lymphocytes, macrophages) [31,36,138], and reduce airway smooth muscle cell proliferation [43], oxidative stress [129], fibrosis [44], cytokine production [34,139], and mucus production [140]. The statins also induce apoptosis in cancerous or proliferative cells and airway mesenchymal cells [141], enhance macrophage efferocytosis [142], increase endothelial cell nitric oxide production [37], and improve cell barrier integrity [143].

Figure 3. The chemical structure of simvastatin

Statins exist in equilibrium between the lactone inactive form (‘closed ring’) and acid active form (‘open ring’). The acid form of statins is the ‘HMG-like’ structure that binds the HMGCR enzyme active site. This HMG-like structure is present in all statins. In vivo, these two chemical forms are in equilibrium. The conversion from lactone to acid depends on the activity of several different classes of enzymes including lactonases, paraoxonases, alkaline hydrolases, and carboxylesterases.