The counter-intuitive role of the neutrophil in the acute respiratory distress syndrome

Abstract

Introduction Neutrophils are the primary effectors of the innate immune system but are profoundly histotoxic cells. The acute respiratory distress syndrome (ARDS) is considered to be a prime example of neutrophil-mediated tissue injury. Sources of data The information presented in this review is acquired from the published neutrophil cell biology literature and the longstanding interest of the senior authors in ARDS pathogenesis and clinical management. Areas of agreement Investigators in the field would agree that neutrophils accumulate in high abundance in the pulmonary microcirculation, lung interstitium and alveolar airspace of patients with ARDS. ARDS is also associated with systemic neutrophil priming and delayed neutrophil apoptosis and clearance of neutrophils from the lungs. In animal models, reducing circulating neutrophil numbers ameliorates lung injury. Areas of controversy Areas of uncertainty include how neutrophils get stuck in the narrow pulmonary capillary network—whether this reflects changes in the mechanical properties of primed neutrophils alone or additional cell adhesion molecules, the role of neutrophil sub-sets or polarization states including pro-angiogenic and low-density neutrophils, whether neutrophil extracellular trap (NET) formation is beneficial (through bacterial capture) or harmful and the potential for neutrophils to participate in inflammatory resolution. The latter may involve the generation of specialized pro-resolving molecules (SPMs) and MMP-9, which is required for adequate matrix processing. Growing points Different and possibly stable endotypes of ARDS are increasingly being recognized, yet the relative contribution of the neutrophil to these endotypes is uncertain. There is renewed and intense interest in understanding the complex ‘new biology’ of the neutrophil, specifically whether this cell might be a valid therapeutic target in ARDS and other neutrophil-driven diseases and developing understanding of ways to enhance the beneficial role of the neutrophil in the resolution phase of ARDS. Areas timely for developing research Aside from treatment of the precipitating causes of ARDS, and scrupulous fluid, infection and ventilation management, there are no pharmacological interventions for ARDS; this represents an urgent and unmet need. Therapies aimed at reducing overall neutrophil numbers risk secondary infection; hence better ways are needed to reverse the processes of neutrophil priming activation, hyper-secretion and delayed apoptosis while enhancing the pro-resolution functions of the neutrophil.

The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host

“…Neutrophils sequestered in the lung rapidly accumulate in the alveolar space where gas exchange is substantially impaired due to oedema and alveolar collapse. Here, excessive neutrophil activation, including the degranulation of histotoxic proteins and pro-inflammatory cytokines, propagate diffuse host lung damage with high mortality [125]. In a murine model of hypoxia-induced acute lung injury, abrogation of hypoxic neutrophil survival by treatment with intra-tracheal IL-4 was able to promote resolution of inflammation and resulted in reduced bronchoalveolar lavage NE content, although the direct effect of IL-4 on degranulation was not assessed in this study [126].…”

NETosis: Molecular Mechanisms, Role in Physiology and Pathology

“…The recent clinical trial (conducted prior to the onset of the COVID-19 pandemic) showed correlation between the NETs content and severity of the community-acquired pneumonia [ 92 ]. Acute lung injury (ALI) and ARDS of various etiologies are accompanied by excessive NETosis (see review [ 93 ]). NETs in these pathologies may be involved in the damage of alveolar epithelium and endothelium.…”

“…Recombinant DNase I has been successfully used in almost all models of pathologies associated with NETosis. In particular, introduction of DNase I significantly facilitates the course of ARDS [ 93 ] and COPD [ 94 ] in animal models. In patients with cystic fibrosis, DNase inhalation improved lung function, and neutrophil elastase facilitated sputum dissolution making it more accessible for DNase [ 110 ].…”

Understanding the role of neutrophils in acute respiratory distress syndrome

“…These chemoattractive signals are recognized by local immune cells, which produce inflammatory mediators that further boost neutrophil recruitment. In ARDS, endothelial cells activate and capture circulating neutrophils [ 31 , 32 ]. Neutrophils are sequestered through selectin-mediated binding, triggering “inside-out” activation of integrins, such as CD11a/CD18, which binds to intercellular adhesion molecules (ICAMs) from the endothelium [ 33 ].…”