Pharmacological approaches to regulate neutrophil activity

Although indispensable in host defense against microbial pathogens, misdirected hyperacute and chronic activation of neutrophils presents the potential hazard of tissue damage, organ dysfunction, and carcinogenesis. In many clinical settings, particularly inflammatory disorders of the airways, over-reactivity of neutrophils is exacerbated by their relative resistance to conventional, pharmacological anti-inflammatory therapies, including, but not limited to, corticosteroids. Notwithstanding their sheer numbers, which can increase rapidly and dramatically during inflammatory responses, these cells are not only pre-programmed to release reactive oxygen species, proteinases, and eicosanoids/prostanoids immediately on exposure to pro-inflammatory stimuli but may also subsequently undergo the process of netosis, thereby enhancing and protracting their inflammatory potential. All of these mechanisms are likely to underpin the resistance of neutrophils to pharmacological control and have triggered the search for alternatives to corticosteroids. In addition to macrolides and adenosine 3',5'-cyclic adenosine monophospate-elevating agents, more recent innovations in the control of neutrophilic inflammation include activators of histone deacetylases and antagonists of chemokine receptors, as well as monoclonal antibodies which target neutrophil-activating cytokines and their receptors. These and other neutrophil-targeted strategies represent the focus of the current review.