Kinase inhibitors in the treatment of obstructive pulmonary diseases

Highlights

• Obstructive pulmonary disease is caused by inflammation.

• Inflammatory signals activate kinase signaling pathways.

• Kinases regulate transcription factors that modulate the proliferative and secretive functions of airway cells.

• Chronic inflammation leads to airway remodeling and exacerbation of airflow obstruction.

• Kinase inhibitors may mitigate airway remodeling and pathology of obstructive pulmonary disease.

Chronic pulmonary diseases, including chronic obstructive pulmonary disease (COPD) and asthma, are major causes of death and reduced quality of life. Characteristic of chronic pulmonary disease is excessive lung inflammation that occurs in response to exposure to inhaled irritants, chemicals, and allergens. Chronic inflammation leads to remodeling of the airways that includes excess mucus secretion, proliferation of smooth muscle cells, increased deposition of extracellular matrix proteins and fibrosis. Protein kinases have been implicated in mediating inflammatory signals and airway remodeling associated with reduced lung function in chronic pulmonary disease. This review will highlight the role of protein kinases in the lung during chronic inflammation and examine opportunities to use protein kinase inhibitors for the treatment of chronic pulmonary diseases.

Introduction

Asthma and chronic obstructive pulmonary disease (COPD) are the two most common chronic pulmonary diseases, affecting approximately 300 million and 250 million individuals worldwide, respectively, and causing 250 000 and 3.1 million deaths annually, respectively [1]. Asthma and COPD share symptoms of cough and dyspnea, the presence of chronic airway inflammation driven by exposure to inhaled immune stimuli, airway wall thickening, and the contribution of cellular senescence of airway epithelium. But the two diseases differ in the segment of the bronchial tree affected, the nature of the inflammation, the inciting immune stimulants, and their long-term course.

In asthma, the entire airway is involved while in COPD, pathologic changes are most pronounced in the small airways. Inflammation in asthma is typically allergen-driven and IgE-driven, and involves TH2 lymphocytes, mast cells and eosinophils [2]. In COPD, inflammation is driven by inhaled toxins and irritants, including those in tobacco smoke, non-tobacco biomass smoke, air pollution, and inhaled endotoxin, and is characterized by TH1 and TH17 lymphocytes, CD8+ lymphocyte predominance, neutrophil infiltration, and macrophage activation [3^••]. Inhaled therapy with short-acting and long-acting beta agonists and corticosteroids are effective in both diseases. However, airway obstruction in asthma is usually more reversible with beta agonist therapy and more responsive to corticosteroid therapy than in COPD [4^•]. Corticosteroids have been shown to reduce the rate of exacerbations, airway inflammation, and the rate of quality of life deterioration in COPD patients; however, an increased risk of pneumonia along with local and systemic adverse effects has also been observed [5]. Inhaled long-acting muscarinic agonists are more effective in COPD than asthma [6^•]. More recently a growing number of injectable biologics targeting specific inflammatory pathways have become available for treating subclasses of asthma, but do not appear to be effective in most patients with COPD. It should be noted that asthma and COPD are both heterogenous diseases with a substantial overlap between the two, including a defined asthma-COPD overlap syndrome [7].

The chronic release of inflammatory cytokines and growth factors from epithelial and immune cells enhances protein kinase signalling pathways and underlies the pathology of asthma and COPD. Several cytokines and growth factors are implicated in chronic pulmonary disease and include the interleukins (IL) IL-1β IL-4, IL-5, IL-6, IL-13, IL-17A, IL-27, IL-33, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF) [8^•,9, 10, 11, 12, 13]. Many protein kinases have been implicated in the signal transduction pathways linking inflammatory mediators and the hyper-contractility of airways, mucus hypersecretion, immune cell infiltration, and airway remodelling that leads to debilitating lung function observed in chronic pulmonary disease [14,15^•]. Figure 1 summarizes protein kinases that are involved in the pathology of asthma and COPD.

Inflammatory signals mediate the pathology of obstructive lung disease through the activation of protein kinase activity [16]. Cytokine receptors (CR) and receptor tyrosine kinases (RTK) at the plasma membrane communicate cytokine and growth factor signals through several mitogen-activated protein (MAP) kinases, phosphatidylinositide 3-kinases (PI3K), and Janus kinases (JAK). Inflammation causes increased adenosine generation, which via activation of G-protein coupled adenosine receptors (A_2BAR) and downstream kinase signalling cascades, contributes to the pathologic changes in asthma and COPD [17]. Gene expression associated with inflammation and tissue remodelling is regulated predominantly by a subset of transcription factors that include nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), cAMP response element-binding protein (CREB), and signal transducer and activator of transcription (STAT) proteins [18].

MAP kinases that respond to cellular stress, such as the c-Jun N-terminal kinases (JNK) and p38 MAP kinases, have long been implicated in mediating inflammatory signals relevant to lung disease [16,19]. However, to date, none of the JNK or p38 MAP kinase inhibitors have shown efficacy in clinical trials and are dose limiting due to unwanted toxicity and side effects. Targeted inhibition of pro-inflammatory p38 MAP kinase substrates such as mitogen-activated protein kinase activated protein kinase-2 (MAPKAPK-2 or MK2) may overcome toxicity issues associated with p38 inhibitors and treating chronic pulmonary disease [20^•]. MK2 is a mediator of inflammatory signals such as TNF-α, IL-6, and IL-1β so MK2 mediators might further reduce the inflammatory response [21]. Eynott et al. provided evidence that targeted inhibition of JNK could mitigate allergen-induced inflammation and proliferation of airway epithelial and smooth muscle cells [22]. While one phase II clinical trial evaluating the JNK inhibitor Tanzisertib for treating idiopathic pulmonary fibrosis ended due to lack of efficacy, no JNK inhibitors are currently being tested for asthma or COPD.

Mitogen activation of the extracellular signal-regulated kinases (ERK) MAP kinases in airway smooth muscle (ASM) cells stimulates cell proliferation and subsequent airway remodelling associated with asthma [23]. This was supported by studies that showed that serum from atopic asthma patients enhanced the expression of cyclin D1, which increases proliferation of human ASM cells [24]. Activated ERK signalling enhances cell proliferation by increasing the expression of cyclin D1.

There is evidence that protein kinases associated with deregulated angiogenesis contribute to the progression of chronic lung disease including COPD [25^•]. Angiogenic factors such as cytokines and growth factors that are released as a result of obstructive pulmonary disease progression leads to the stimulation of direct and indirect proangiogenic markers that generate and stabilize new blood vessels [26^•]. This microvascular dysfunction leads to re-modulation and inflammation of the bronchi. Recent studies suggest that targeted inhibition of inflammation-mediated activation of the receptor tyrosine kinases vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor-2 (FGFR-2) reduces angiogenesis associated with lung remodelling in COPD [26^•]. Similarly, a small clinical study suggested that inhibition of PDGF and the related c-Kit receptor tyrosine kinase with Masitinib is effective in severe corticosteroid-dependent asthma [27].

In COPD patients, protein kinases play an important role in the loss of tissue architecture by enhancing degradation of the extracellular matrix by proteinases such as matrix metalloproteinases-9 (MMP-9) [28]. Proinflammatory triggers including allergens, cigarette smoke, bacterial lipopolysaccharides (LPS), interleukins (IL-17 and IL-1β), and other inflammatory signals that induce an oxidative stress response, activate MAP kinases and PI3K signalling, which enhances AP-1-mediated expression of MMP-9 [22,29,30,31^•]. Another key regulator of inflammatory signals is the NF-κB transcription factor. Targeted inhibition of the inhibitor of κB kinase (IKK) is a potential approach to prevent NF-κB translocation to the nucleus and inflammatory gene expression. The status of past and current clinical trials evaluating protein kinase inhibitors for treatment of asthma or COPD is listed in Table 1.