New Pharmacological Tools to Target Leukocyte Trafficking in Lung Disease

Abstract

Infection and inflammation of the lung results in the recruitment of non-resident immune cells, including neutrophils, eosinophils and monocytes. This swift response should ensure clearance of the threat and resolution of stimuli which drive inflammation. However, once the threat is subdued this influx of immune cells should be followed by clearance of recruited cells through apoptosis and subsequent efferocytosis, expectoration or retrograde migration back into the circulation. This cycle of cell recruitment, containment of threat and then clearance of immune cells and repair is held in exquisite balance to limit host damage. Advanced age is often associated with detrimental changes to the balance described above. Cellular functions are altered including a reduced ability to traffic accurately towards inflammation, a reduced ability to clear pathogens and sustained inflammation. These changes, seen with age, are heightened in lung disease, and most chronic and acute lung diseases are associated with an exaggerated influx of immune cells, such as neutrophils, to the airways as well as considerable inflammation. Indeed, across many lung diseases, pathogenesis and progression has been associated with the sustained presence of trafficking cells, with examples including chronic diseases such as Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis and acute infections such as Pneumonia and Pneumonitis. In these instances, there is evidence that dysfunctional and sustained recruitment of cells to the airways not only increases host damage but impairs the hosts ability to effectively respond to microbial invasion. Targeting leukocyte migration in these instances, to normalise cellular responses, has therapeutic promise. In this review we discuss the current evidence to support the trafficking cell as an immunotherapeutic target in lung disease, and which potential mechanisms or pathways have shown promise in early drug trials, with a focus on the neutrophil, as the quintessential trafficking immune cell.

Keywords: ageing; chemotaxis; monocyte; neutrophil (PMN); proteinase; respiratory.

Figure 1

Immune response to inflammation and infection. Upon insult, either due to pathogen or sterile injury, resident immune cells such as macrophage are ready to respond and promote the recruitment of monocytes and neutrophils via activation of the endothelium. As part of the response, monocytes differentiate in the tissue to macrophage and these cells become activated to respond to the insult, promoting further recruitment of other immune cells such as T cells and carrying out effector functions including phagocytosis and NETosis. In health, resolution follows by death of neutrophils and clearance by efferocytosis, promoting the release of anti-inflammatory cytokines and repair. In disease, the persistent recruitment of immune cells and potential impaired effector functions of these cells perpetuate inflammation and damage.

Figure 2

Molecular targets for altering leukocyte trafficking. Multiple receptors and proteins have been targeted to alter leukocyte trafficking. Chemokine receptors CXCR1, CXCR2, CXCR4 CCR5 and CCR6 have all been investigated either using pharmacological intervention or in early studies with gene knockout models. Within the cell, key enzymes such as phosphoinositide 3-kinase (PI3K) and β-Hydroxy β-methylglutaryl-CoA reductase (HMG CoAR) that have been implicated in cell motility.