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Published in final edited form as: Surgery. 2024 Feb 10;175(5):1346–1351. doi: 10.1016/j.surg.2024.01.002

An Engineered Poly(A) Tail Attenuates Gut Ischemia/Reperfusion-Induced Acute Lung Injury

Atsushi Murao 1, Alok Jha 1, Monowar Aziz 1,2, Ping Wang 1,2,*
PMCID: PMC11001521  NIHMSID: NIHMS1961529  PMID: 38342730

Abstract

Background:

Gut ischemia/reperfusion (I/R) causes the release of damage-associated molecular patterns (DAMPs), leading to acute lung injury (ALI) and high mortality. Cold-inducible RNA-binding protein (CIRP) is an RNA chaperon that binds poly(A) tail of mRNA intracellularly. Upon cell stress, CIRP is released and extracellular CIRP (eCIRP) acts as a DAMP, worsening inflammation. To inhibit eCIRP, we have recently developed an engineered poly(A) tail named A12. Here, we sought to investigate the therapeutic potential of A12 in gut I/R-induced ALI.

Methods:

Male C57BL6/J mice underwent superior mesenteric artery occlusion and were treated with intraperitoneal A12 (0.5 nmol/g BW) or vehicle at the time of reperfusion. Blood and lungs were collected 4 h after gut I/R. Systemic levels of eCIRP, IL-6, AST, ALT, and LDH were determined. The pulmonary gene expression of cytokines (IL-6, IL-1β) and chemokines (MIP2, KC) was also assessed. In addition, lung MPO, injury score, and cell death were determined. Mice were monitored for 48 h after gut I/R for survival assessment.

Results:

Gut I/R significantly increased the serum eCIRP levels. A12 treatment markedly reduced the elevated serum IL-6, ALT, AST, and LDH by 53%, 23%, 23%, and 24%, respectively in gut I/R mice. A12 also significantly decreased cytokine and chemokine mRNAs and MPO activity in the lungs of gut I/R mice. Histological analysis revealed that A12 attenuated tissue injury and cell death in the lungs of gut I/R mice. Finally, administration of A12 markedly improved survival of gut I/R mice.

Conclusions:

A12, a novel eCIRP inhibitor, diminishes inflammation and mitigates ALI when employed as a treatment during gut I/R. Hence, the targeted approach towards eCIRP emerges as a promising therapeutic strategy for alleviating gut I/R-induced ALI.

Keywords: Poly(A), Ischemia/Reperfusion, Acute Lung Injury, eCIRP

Graphical Abstract

This study demonstrates the effectiveness of a novel eCIRP inhibitor, poly(A) mRNA mimic A12, to attenuate inflammation and acute lung injury, and improve survival in mice with gut I/R injury. These findings support the promising therapeutic potential of A12 for treating gut I/R-induced lung injury.

Introduction

Gut ischemia/reperfusion (I/R) injury is a common surgical complication with up to 50% mortality rate even if recognized and treated within 24 h (1, 2). It is important to restore the blood flow and reoxygenate the hypoxic tissues promptly to prevent the ischemic site from necrosis (3, 4). On the contrary, reperfusion causes the release of inflammatory intracellular components, namely damage-associated molecular patterns (DAMPs), into the circulation (2, 5, 6). Consequently, DAMPs upregulate cytokines and chemokines in remote organs and induce the influx of hyperactivated immune cells, such as neutrophils. The lungs are susceptible to the exposure to inflammatory mediators and infiltrating neutrophils (7). Gut I/R often results in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) (7, 8).

Cold-inducible RNA-binding protein (CIRP) is an 18-kD RNA chaperone that binds poly(A) tail of mRNA to regulate the translation of its target mRNA inside the cells under the steady state (9, 10). However, when the cells are stressed by hypoxia or activated by pathogen-nassociated molecular patterns (PAMPs), CIRP is released into the extracellular space to serve as a DAMP (9–13). Extracellular CIRP (eCIRP) activates pattern recognition receptors (PRRs), including Toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells-1 (TREM-1), to induce inflammatory responses, such as cytokine production (9, 10, 14). eCIRP has been shown to significantly contribute to systemic inflammation and ALI in sepsis and gut I/R injury (9, 10, 15). Thus, targeting eCIRP would be a novel therapeutic for inflammatory diseases.

Given the CIRP’s property of binding poly(A) tail, we have recently developed a novel eCIRP inhibitor consisting of twelve adenosines (A) to mimic the poly(A) tail of mRNA (16). To protect it from nuclease degradation and improve its stability, we methylated 2′-O ribose in every nucleotide and incorporated terminal phosphorothioate linkages. This novel oligonucleotide drug, named A12, strongly and specifically bound eCIRP and significantly inhibited eCIRP from binding to its receptor TLR4, preventing cytokine production in macrophages. We further tested its efficacy in a mouse model of sepsis and found that A12 significantly inhibited inflammation and ALI and improved survival in septic mice (16).

Since eCIRP is partially responsible for unfavorable outcomes in not only sepsis but also gut I/R, we sought to investigate the therapeutic potential of A12 in gut I/R in the present study. Here, we demonstrated that A12 attenuated inflammation, inhibited neutrophil infiltration into the lungs, alleviated ALI, and improved survival in a mouse model of gut I/R injury.

Materials and Methods

Animals and synthesis of A12

Male C57BL/6 mice, 8–12-week-old, were purchased from Charles River Laboratories (Wilmington, MA). Mice were housed in a temperature-controlled room with 12-hour (h) intermittent light and dark cycles and fed a standard mouse chow diet with water. All animal experiments were preformed following the National Institutes of Health guidelines for the care and use of laboratory animals and were approved by our Institutional Animal Care and Use Committee (IACUC). A12 (AAAAAAAAAAAA, with 2′-O-methyl ribose modifications throughout the nucleotides and terminal phosphorothioate linkages) was synthesized by Integrated DNA Technologies (Coralville, IA).

Mouse model of gut I/R injury

We induced gut I/R in mice by superior mesenteric artery occlusion as we previously reported (17) and described in Supplemental Methods. 4 h after the surgery, the blood and lungs were harvested. Serum levels of eCIRP, IL-6, AST, ALT, and LDH, and lung IL-6, IL-1β, MIP2, KC, MPO, injury score, and cell death were determined as described in Supplemental Methods. A 48-h survival study was also conducted.

Statistical analysis

Data represented in the figures are expressed as mean ± SEM. ANOVA was used for one-way comparison among multiple groups, and the significance was determined by the Student Newman-Keuls (SNK) test. The paired Student’s t-test was applied for two-group comparisons. Survival rates were analyzed by the Kaplan-Meier estimator and compared using a log-rank test. Significance was considered for p ≤ 0.05 between study groups. Data analyses were carried out using GraphPad Prism graphing and statistical software (GraphPad Software, San Diego, CA).

Results

A12 attenuates serum IL-6 and organ injury markers in gut I/R mice

eCIRP levels in the serum were significantly increased after gut I/R by 15-fold compared to sham mice (Figure 1A). We found that IL-6 was significantly elevated in the serum of gut I/R mice administered with a vehicle (Figure 1B). In addition, organ injury markers, AST, ALT, and LDH, were also significantly elevated in the serum of gut I/R mice (Figure 1C–E). However, IL-6, AST, ALT, and LDH levels were significantly lower in the serum of gut I/R mice treated with A12 by 53%, 23%, 23%, and 24%, respectively compared to vehicle-treated mice (Figure 1B–E). These data indicate that A12 attenuates gut I/R-induced systemic inflammation as reflected by serum cytokine and organ injury markers.

Figure 1. A12 attenuates serum cytokine and organ injury markers in gut I/R mice.

Figure 1.

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Mice were induced gut I/R by SMA occlusion for 45 min. 4 h after the surgery, the blood was harvested. (A) Serum levels of eCIRP in sham and gut I/R (II/R) mice. Experiments were performed 3 times, and all data were used for analysis. Data are expressed as mean ± SEM (n=4–6 samples/group) and compared by paired student’s t-test. *p < 0.05 vs. Sham. A vehicle or 0.5 nmol/kg A12 was i.p. instilled at the time of reperfusion, and the blood was harvested 4 h after the surgery. Serum levels of (B) IL-6, (C) AST, (D) ALT, and (E) LDH. Data are expressed as mean ± SEM (n=9 samples/group) and compared by one-way ANOVA and SNK test. *p < 0.05 vs. sham, #p < 0.05 vs. vehicle.

A12 attenuates lung inflammation and neutrophil influx in gut I/R mice

Subjecting mice to gut I/R upregulated the mRNA levels of IL-6, IL-1β, KC and MIP2 in the lung tissues compared to sham mice (Figure 2A–D). In addition, MPO activity in the lungs was increased in gut I/R mice compared to sham mice, indicating increased neutrophil infiltration after gut I/R (Figure 2E). Notably, treatment with A12 significantly attenuated the mRNA levels of IL-6, IL-1β, KC, and MIP by 72%, 43%, 57%, and 48%, respectively in the lung tissues compared to vehicle treatment (Figure 2A–D). We also found that MPO activity in the lung was significantly reduced by 33% with A12 treatment (Figure 2E). Taken together, it is indicated that administration of A12 attenuates lung inflammation and neutrophil accumulation in gut I/R mice.

Figure 2. A12 attenuates lung inflammation and neutrophil influx in gut I/R mice.

Figure 2.

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The lungs were harvested 4 h after gut I/R with A12 treatment. mRNA levels of (F) IL-6, (G) IL-1β, (H) KC, and (I) MIP-2, and (J) MPO activity in the lungs are shown. Data are expressed as mean ± SEM (n=9 samples/group) and compared by one-way ANOVA and SNK test. *p < 0.05 vs. sham, #p < 0.05 vs. vehicle.

A12 attenuates lung injury in gut I/R mice

Severe tissue damage was observed in the lungs of vehicle-administered gut I/R mice compared to sham mice (Figure 3A). The lungs of vehicle-administered gut I/R mice showed significantly worse lung injury scores compared to that of sham mice (Figure 3B). However, treatment of gut I/R mice with A12 significantly alleviated lung injury compared to vehicle-administered gut I/R mice (Figure 3A, B). This data indicates that A12 treatment mitigates lung injury in gut I/R mice.

Figure 3. A12 attenuates lung injury in gut I/R mice.

Figure 3.

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4 h after gut I/R with A12 treatment, the lungs were harvested for histological analysis. (A) Representative images of H&E-stained lung tissues. Magnification 200×. Scale bar: 100 μm. (B) Lung injury scores based on a scoring system for acute lung injury in experimental animals as outlined by the American Thoracic Society. Experiments were performed 3 times, and all data were used for analysis. Data are expressed as mean ± SEM (n=6 samples/group) and compared by one-way ANOVA and SNK test. *p < 0.05 vs. sham, #p < 0.05 vs. vehicle.

A12 attenuates cell death in the lungs of gut I/R mice

TUNEL staining, which visualizes dead cells, revealed that the number of dead cells was significantly increased in the lungs by the gut I/R surgery when the mice were administered with a vehicle. Meanwhile, treatment with A12 significantly reduced the number of dead cells in the lungs compared to the vehicle administration in gut I/R mice (Figure 4A, B). This data indicates that A12 prevented cell death in the lungs, further supporting the alleviation of lung injury by A12 treatment in gut I/R mice.

Figure 4. A12 attenuates cell death in the lungs of gut I/R mice.

Figure 4.

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4 h after gut I/R with A12 treatment, the lungs were harvested for evaluating cell death in the tissues. (A) Representative images of TUNEL staining (green fluorescence) and nuclear counterstaining (blue fluorescence). Magnification 200×. Scale bar: 100 μm. (B) Numbers of TUNEL positive cells/HPF in lung tissues. Experiments were performed 3 times, and all data were used for analysis. Data are expressed as mean ± SEM (n=6 samples/group) and compared by one-way ANOVA and SNK test. *p < 0.05 vs. sham, #p < 0.05 vs. vehicle.

A12 improves survival in gut I/R mice

Finally, we found that the administration of A12 significantly improved survival in this highly lethal model from 0% to 33% (Figure 5). Thus, it is indicated that A12 not only mitigates inflammation and alleviates ALI, but also improves survival in gut I/R injury (Figure 6).

Figure 5. A12 improves survival in gut I/R mice.

Figure 5.

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48 h survival study of gut I/R mice with i.p. administration of a vehicle or 0.5 nmol/g A12. n = 15 mice/group. Survival rates were analyzed by the Kaplan-Meier estimator using a log-rank test. *p < 0.05 vs. vehicle.

Figure 6. Summary of findings.

Figure 6.

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Gut I/R causes to the release of eCIRP, which activates cells to produce inflammatory mediators and induces neutrophil influx in the lungs, leading to ALI and death. A12 neutralizes eCIRP to improve the outcomes of gut I/R injury.

Discussion

In the present study, we have demonstrated that the novel eCIRP inhibitor, poly(A) mRNA mimic A12, attenuated inflammatory mediators in the blood and lungs, inhibited neutrophil infiltration into the lungs, alleviated ALI, and improved survival in gut I/R mice (Figure 6). Clinically, it is prioritized to restore the blood flow as promptly as possible during gut ischemia since the direct organ damage would be irreversible when the reoxygenation of the tissue is not achieved within the therapeutic time window, i.e., before it becomes necrotic (1, 3). However, reperfusion can cause damage in remote organs due to the release of inflammatory mediators from the ischemic site into the circulation (7). This aspect is often overlooked especially at the bedside, and no definitive therapies focusing on remote organ dysfunctions in gut I/R have been established clinically as of now (3). Since the injury in remote organs is not due to the direct effects of hypoxia, it could be preventable or reversible by targeting the mediators causing the organ injury. The lungs are extremely vulnerable to the exposure to those mediators, and ALI is a common complication of operation and gut I/R (7, 8, 18). Together with our previous study showing that eCIRP contributed to ALI in gut I/R (19), we focused on the lungs and evaluated the therapeutic potential of A12 in the present study.

Different kinds of oligonucleotide drugs or vaccines have been produced lately and some of them are already being used in the clinical settings (20–22). 2′-O-methylation and phosphorothioate linkages, which are implemented in A12, are the most widely used modifications for oligonucleotide drugs, supporting the safety of these modifications (20, 23). Regarding the mechanistic novelty of A12, it should be noted that the most of other oligonucleotide drugs, often encapsulated in nanoparticles, are designed to act intracellularly to modulate gene and protein expressions (20, 23, 24). On the contrary, in our previous paper, we have demonstrated that A12 bound eCIRP in the extracellular space and neutralized it to inhibit the ligand-receptor interaction (16). Our approach focusing on the extracellular application of oligonucleotides would potentially provide new insight in the pharmacological field.

The clinical significance of our study is pinpointed by the incorporation of key clinical parameters used for diagnosing the disease status in patients with gut I/R. Specifically, our study focuses on the assessment of AST, ALT, and LDH in the blood and neutrophil influx in the lungs. Notably, elevated levels of AST, ALT, and LDH are commonly observed in gut I/R patients and have been established as significant indicators of the disease (25–27). Additionally, an increased neutrophil content in the blood has been reported in these patients (25, 28, 29), which is associated with heightened neutrophil infiltration into the lungs. Our research has demonstrated that the administration of A12 effectively mitigates the elevation of serum AST, ALT, and LDH levels, and reduces lung neutrophil infiltration. This compelling evidence suggests that A12 holds promise in improving the clinical outcomes of gut I/R patients.

For the next steps to identify clinically relevant information about the use of A12 in gut I/R, it would be valuable to accumulate comprehensive datasets of gut I/R patients. The currently available clinical data of gut I/R are mostly limited to blood count and serum/plasma biomarkers (25). Besides those existing parameters, the status of cellular molecules and pathways, especially the ones potentially affected by A12, is worth evaluating in human samples to support our findings. Transcriptomic and proteomic analysis would be highly useful for this purpose. For example, single-cell RNA sequencing enables us to comprehensively screen genetic status in individual cells and further determine the altered pathways based on those genes (30, 31). The potential efficacy of A12 for gut I/R patients would become much more convincing by comprehensively confirming the similarity in plethora of biomarkers and pathways between animal and human data in gut I/R and evaluating the effects of A12 on those parameters in animals using transcriptomic and proteomic analysis. The assessment of A12’s efficacy in human cell culture system and comparing it with our previous findings in mouse cells would also strengthen the clinical relevance (16). In addition, in vitro usage of human cells is recommended for the toxicity assessment of oligonucleotide drugs since their potential off-target effects are known to be sequence-dependent and therefore species-specific (32, 33). Together, these future human-relevant studies would be of significance for the advancement of A12 to the next stage of drug development.

With an aim toward achieving A12 as a therapeutic tool for the treatment of gut I/R, the pharmacological properties of this drug need to be delineated more in details. We instilled A12 into mice at the time of reperfusion in this study. Testing the efficacy of A12 administration at later time points would be informative to determine the therapeutic time window of this drug in gut I/R. In addition, A12 was only administered once throughout the experiments. It would be interesting to evaluate whether repetitive administration of A12 can further improve the outcomes of gut I/R. Moreover, the effects of A12 on different severities of gut I/R are another important pharmacological information to be investigated. While we used an extremely lethal disease model, i.e., 100% mortality with vehicle treatment, in this study, testing A12’s efficacy in less severe models of gut I/R, such as 50% mortality with vehicle treatment, by changing the ischemic time should also be considered in the future. Oligonucleotide drugs are mainly metabolized by exonucleases in the plasma and excreted by the kidneys (33). The pharmacokinetics (PK) of oligonucleotide drugs implemented with the same chemical modifications as A12, i.e., 2′-O-methyl ribose and phosphorothioate linkages, are well tested across species (33). In our previously published study, the half-life of A12 was determined to be 2 h and no apparent abnormal accumulation was observed (16). Nevertheless, the dose and frequency of A12 administration could require adjustment according to the renal function.

Another important aspect in the clinical utilization of medicine is rigorous safety evaluation. As to the possible safety concerns, oligonucleotide drugs in general have the potential to stimulate intracellular nucleotide-sensing PRRs, such as TLR7 and TLR9, to induce possible off-target inflammatory responses (34). The activation of those receptors could result in the production of cytokines including, but not limited to, IL-1β, IL-6, and type I interferons (34). These cytokines might further activate different immune and non-immune cells, potentially causing tissue damage or blood clot (35, 36). Even though we have previously found that A12 alone had no apparent effects on unstimulated macrophages and healthy rodents especially in cytokine production (16), the assessments of organ injury and blood coagulation are important for A12’s safety evaluation. Determination of LD50 and testing in higher animals are also required to confirm the safety of A12 for its future clinical application.

The current research aims to investigate the therapeutic potential of a new anti-inflammatory oligonucleotide drug in gut I/R. For this purpose, our study consists solely of translational experiments in vivo to make the study design straightforward rather than elucidating its potentially intricate mechanisms of action. As to the next steps, we discussed human-related studies such as transcriptomic and proteomic analysis of patient database and utilization of human cells along with the determination of pharmacokinetics (PK), safety evaluations, and testing in higher animals, all of which are important for the advancement of A12 to clinical trials. We also mentioned that oligonucleotide drugs have already been used clinically, smoothening the transition of this type of drugs from bench to bedside especially for FDA approval. In the future clinical trials, the safety of A12 at a variety of doses as well as its distribution, metabolism, and excretion would be evaluated in healthy volunteers. Later, efficacy and safety would be evaluated with patients and the dose would be optimized, followed by a comparison to placebo. These sequential processes would eventually lead A12 to becoming a potential therapeutic candidate for gut I/R patients.

In summary, gut I/R can cause organ damage in remote organs and this damage could be prevented by targeting eCIRP responsible for organ injury. A12 exhibits the capacity to mitigate inflammation and ALI, leading to enhanced survival in mice subjected to gut I/R. Thorough evaluations of its efficacy and safety in larger animal models are eagerly anticipated, paving the way for the clinical utilization of A12.

Supplementary Material

1

Funding/Support

M.A. is supported by the National Institutes of Health (NIH) grants R01GM129633 and P.W. is supported by NIH grants R01HL076179 and R35GM118337. We acknowledge the BioRender software service for preparing the visual abstract.

Abbreviations

A12

AAAAAAAAAAAA

I/R

ischemia-reperfusion

ALI

acute lung injury

DAMP

damage-associated molecular pattern

eCIRP

extracellular cold-inducible RNA-binding protein

AST

aspartate aminotransferase

ALT

alanine aminotransferase

LDH

lactate dehydrogenase

MPO

myeloperoxidase

Footnotes

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Conflict of Interest/Disclosure

The authors declared that they have no competing interests.

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Associated Data

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NIHMS1961529-supplement-1.docx (18.6KB, docx)

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