Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Abstract

Neutrophils have a prominent role in all human immune responses against any type of pathogen or stimulus. The lungs are a major neutrophil reservoir and neutrophilic inflammation is a primary response to both infectious and non-infectious challenges. While neutrophils are well known for their essential role in clearance of bacteria, they are also equipped with specific mechanisms to counter viruses and fungi. When these defense mechanisms become aberrantly activated in the absence of infection, this commonly results in debilitating chronic lung inflammation. Clearance of bacteria by phagocytosis is the hallmark role of neutrophils and has been studied extensively. New studies on neutrophil biology have revealed that this leukocyte subset is highly adaptable and fulfills diverse roles. Of special interest is how these adaptations can impact the outcome of an immune response in the lungs due to their potent capacity for clearing infection and causing damage to host tissue. The adaptability of neutrophils and their propensity to influence the outcome of immune responses implicates them as a much-needed target of future immunomodulatory therapies. This review highlights the recent advances elucidating the mechanisms of neutrophilic inflammation, with a focus on the lung environment due to the immense and growing public health burden of chronic lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), and acute lung inflammatory diseases such as transfusion-related acute lung injury (TRALI).

The Natural Polypeptides as Significant Elastase Inhibitors

“…Several changes resulted from elastase administration such as disorganized elastin, degradation of proteoglycans, and abnormal collagen remodeling. Regarding the dose and number of elastase challenges, many scientific groups demonstrated that mice subjected to five elastase administrations with a 1-week interval between them developed not only a more severe alveolar destruction, but also systemic manifestations, such as diaphragmatic dysfunction, weight loss, pulmonary arterial hypertension, and exercise intolerance (De et al, 2016;Crocetti et al, 2019;Giacalone et al, 2020). Thus, inhibition of elastase by chemical drugs has also been suggested as a way to recover from different inflammatory diseases.…”

“…However, clinical trials revealed an insufficient therapeutic efficacy of the drug in human severe lung injury and respiratory inflammation (Zeiher et al, 2004). Additionally, sivelestat has the risks of organ toxicity and poor pharmacokinetics (Tsai et al, 2015;Giacalone et al, 2020). The problem in developing new elastase inhibitors is the interference function of elastase with other proteases.…”

“…The recognition of neutrophil elastase as a promising target in chronic inflammatory diseases has increased (Wagner et al, 2016;Dittrich et al, 2018;Giacalone et al, 2020). This is why we have chosen to shed light on natural polypeptides as significant inhibitors of elastases, which could be used as hitto-lead compounds for further development.…”

<p>NLRP3 Regulated CXCL12 Expression in Acute Neutrophilic Lung Injury</p>

“…In sepsis-induced ALI, neutrophils are recruited and primed in the injury site by insults released from activated residential cells in circulation, 3 which subsequently clear the pathogen by efferocytosis, NETosis and proteinases. 4,5 However, the excessive accumulation of primed neutrophils contributes to uncontrolled inflammation and extreme lung damage, which are correlated with poor clinical outcome in ARDS. [6][7][8] In animal models, the depletion of neutrophils reduces the severity of lung injury.…”

Tamoxifen reduces inflammatory infiltration of neutrophils in the airways

“…Neutrophils are immune cells whose function is absolutely necessary for an efficient defensive response, nevertheless, an increase in neutrophil recruitment or a failure in their clearance is associated with collateral tissue damage, delayed or defective healing, and non-resolved inflammation [1,2]. For example, chronic inflammation as observed in cystic fibrosis (CF), non-eosinophilic asthma or chronic obstructive pulmonary disease (COPD), as well as acute inflammatory responses including Covid-19 are often affected by massive neutrophilic infiltration, thus its contention appears necessary [3][4][5][6]. In fact, animal models of acute lung injury (ALI) have provided insight as neutrophil depletion, or inhibition of neutrophil function, invariably ameliorates the extent of damage in the lungs [7].…”