Commentary: Understanding the Impact of Infection, Inflammation and Their Persistence in the Pathogenesis of Bronchopulmonary Dysplasia

Frontiers in Medicine

Jay K. Kolls¹ 

关键词: bronchopulmonary dysplasia;    IL-1;    CXCL8;    CXCR2;    lung diseases;   

DOI  :  10.3389/fmed.2017.00024

学科分类：医学（综合）

来源: Frontiers

【 摘 要 】

As Drs. Balany and Bhandari (1) point out in their recent review, despite the development of surfactant therapy, and new forms of non-invasive ventilation, bronchopulmonary dysplasia (BPD) remains the most common chronic respiratory disease in newborns/infants. The authors point out the key drivers of disease including infection, barotrauma, hyperoxia, and inflammation and highlight the potential role that inflammation plays in driving the disease. Lung inflammation can be triggered by activation of the innate immune system and this can be triggered by cell surface or cytoplasmic receptors that fall into the three key categories—toll-like receptors (TLRs), Nod-like receptors (NLRs), and c-type lectin receptors (CLRs). TLRs 1, 2, 4, and 6 are surface receptors that recognize both exogenous stimuli such as lipopeptides or endotoxin (2) and endogenous ligands such as Hsp70 or oxidized phospholipids (3). Thus, inflammation in BPD could be driven by ligands from invading pathogens in an intubated patient or endogenous ligands that could be released during hyperoxia. One could envision that the therapeutic approach may be different given the proximal driver of inflammation. Thus, it is important to not only to characterize the type of inflammation but we need a keen understanding of what initiated the response. NLRs are cytoplasmic receptors and have several ligands including muramyl dipeptide (2). These receptors play a key role in activation of the inflammasome which is an intracellular protein structure that results in caspase-1 mediated cleavage of proIL-1β or pro-IL-18 into mature secreted proteins. By contrast, other IL-1 family members such as IL-1α or IL-33 can be released and be biologically active independent of caspase-1-mediated cleavage. This pathway is an active area of drug development as there is strong genetic evidence of IL-33 in asthma (4, 5). For ligands that bind IL-1R1, IL-1β, and IL-1α, Anakinra has been FDA approved for the treatment of rheumatoid arthritis and for the treatment of neonatal-onset multisystem inflammatory disease (5). Given that overexpression of IL-1β results in decreased alveolarization (6), this may be a viable target. However, this pathway is also critical for host immunity to several pathogens including influenza (7) and Staphylococcus aureus infection (8), so one would need to proceed with caution and likely exclude patients with active infection. CLRs recognize carbohydrate ligands such as mannans and glucans and drive inflammation but also can be involved in resolution of inflammation as well (9).

【 授权许可】

CC BY