Early local neutralization of CC16 in sepsis‑induced ALI following blunt chest trauma leads to delayed mortality without benefitting overall survival

Abstract

Blunt thoracic trauma (TxT) is a common injury pattern in polytraumatized patients. When combined with a secondary trigger, TxT often results in acute lung injury (ALI), which negatively affects outcomes. Recent findings suggest that ALI is caused by both local and systemic inflammatory reactions. Club cell protein (CC)16 is an anti-inflammatory peptide associated with lung injury following TxT. Recently, the anti-inflammatory properties of endogenous CC16 in a murine model of TxT with subsequent cecal-ligation and puncture (CLP) as the secondary hit were demonstrated by our group. The present study aimed to determine whether CC16 neutralization improves survival following 'double-hit'-induced ALI. For this purpose, a total of 120 C57BL/6N mice were subjected to TxT, followed by CLP after 24 h. Sham-operated animals underwent anesthesia without the induction of TxT + CLP. CC16 neutralization was performed by providing a CC16 antibody intratracheally following TxT (early) or following CLP (late). Survival was assessed in 48 animals for 6 days after CLP. Sacrifice was performed 6 or 24 h post-CLP to evaluate the anti-inflammatory effect of CC16. The results revealed that CC16 neutralization enhanced pro-inflammatory CXCL1 levels, thereby confirming the anti-inflammatory characteristics of CC16 in this model. Early CC16 neutralization immediately following TxT significantly prolonged survival within 60 h; however, the survival rate did not change until 6 days post-trauma. Late CC16 neutralization did not provide any survival benefits. On the whole, the present study demonstrated that neutralizing CC16 confirmed its anti-inflammatory potential in this double-hit ALI model. Early CC16 neutralization prolonged survival within 60 h; however, no survival benefits were observed after 6 days post-CLP in any group.

Narrowing the Gap: Preclinical Trauma With Postinjury Sepsis Model With Increased Clinical Relevance

“…We identified drastic weight loss in groups subjected to trauma with pneumonia compared with injury alone after 2 days. This differs from the findings of Vollrath et al (18), who did not observe weight differences in postinjury sepsis, but this study only subjected male mice to blunt chest trauma and CLP and not multicompartmental injuries. This suggests that more severe injury followed by sepsis results in acute body weight loss.…”

“…There are currently multiple preclinical models in use to study the pathophysiology underlying postinjury sepsis. However, the majority of these models use only male animals, excluding female subjects in these studies (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). There is a paucity of models, which have thus far investigated the response of females to trauma followed by sepsis.…”

“…Diodato et al (21) investigated the effects of hemorrhagic shock and postinjury cecal ligation and puncture (CLP) and found that only males had plasma proinflammatory cytokines and not females. In addition, many models use isolated trauma such as blunt chest injury or extremity fracture followed by sepsis instead of multicompartmental injuries (16)(17)(18)(19)(20). A subset of trauma-sepsis models are of severe injury, but these only included male subjects (9,10).…”

The relationship between the expression of serum IL-18 mRNA, CC16, and sTREM-1 and the severity and prognosis of ventilator-associated pneumonia in elderly patients

“…Interleukin-18 (IL-18) is an important neutrophil chemotactic factor that can promote Th1 cytokine differentiation and Th2 cytokine secretion, produce immunoglobulin E (lgE) and immunoglobulin G (lgG) antibodies, and cause diseases such as immediate hypersensitivity and immune damage (4). Clara cell secretory protein 16 (CC16) is a functional protein secreted by Clara cells that plays a regulatory role in the inflammatory response (5). The soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) belongs to the immunoglobulin superfamily and is often used to diagnose infectious diseases (6).…”

CC16-TNF-α negative feedback loop formed between Clara cells and normal airway epithelial cells protects against diesel exhaust particles exposure-induced inflammation

“…CC16, specifically expressed in distal airway Clara cells, is the most abundant secretory protein in the airway surface fluid, accounting for 5% of the total protein quantity recovered by bronchoalveolar lavage [13]. It is well known that CC16 has anti-inflammatory and antioxidant effects [14][15][16][17][18][19]. The change in CC16 level not only has a profound effect on the composition of the airway surface fluid, but also affects the response of the airway epithelium to environmental stimuli [20][21][22].…”