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The IL-33-ST2 Pathway Contributes to Ventilator-Induced Lung Injury in Septic Mice in a Tidal Volume-Dependent Manner

Ding, Xibing∗,†,‡; Jin, Shuqing∗,‡; Shao, Zhenzhen; Xu, Li‡,§; Yu, Zhuang; Tong, Yao; Chen, Zhixia; Turnquist, Heth; Pitt, Bruce R.||; Billiar, Timothy R.; Zhang, Li-Ming; Li, Quan∗,#

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doi: 10.1097/SHK.0000000000001260
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Mechanical ventilation (MV), a common requisite component of intraoperative care for adequate gas exchange and the delivery of anesthetics in patients with surgical sepsis, is well known to cause the iatrogenic syndrome of ventilator-induced lung injury (VILI) (1–4). VILI may occur during ventilation of a normal lung or worsen pre- and coexisting lung injury (2).

Sepsis is the most common predisposing factor for acute respiratory distress syndrome and acute lung injury (ARDS/ALI) (5) and many sepsis patients require MV. Sensitization to VILI in the setting of preexisting ALI due to pneumonia (6, 7), intratracheal endotoxin (8–10), or sterile injury (11) has been shown in two-hit models, but how MV impacts lung injury in intra-abdominal sepsis is not clear.

Recent studies have advanced our understanding of the functional roles of interleukin (IL)-33 in immune regulation, inflammation, and antimicrobial responses. IL-33 is a member of the IL-1 family, which localized in the nuclei of epithelial and endothelial cells as a nuclear factor, where it has been shown to repress ribonucleic acid transcription. In alveolar type two cells, it also functions as a cytokine when released from cells (12). Increased local and systemic IL-33 levels are observed in patients suffering from various immune-mediated diseases. The receptor complex for IL-33 consists of the specific subunit suppression of tumorigenicity 2 (ST2) and the shared signaling chain, IL-1RAcP (13, 14). The release of IL-33 from living cells was reported in human bronchial epithelium exposed to Alternaria(15) and from mechanically-stressed fibroblasts and pulmonary epithelial cells in vitro and in vivo(16–18). We hypothesized that MV could exacerbate CLP-mediated lung injury through IL-33 and speculated that ventilation mode would correlate with IL-33 upregulation.

Here, we found that ventilation of mice following CLP at a moderate tidal volume (10 mL/kg; MTV) dramatically increased systemic and lung inflammation as well as lung injury in an IL-33- and ST2-dependent manner. In contrast, low tidal volume ventilation (6 mL/kg, LTV) reduced inflammation and injury relative to non-ventilated mice and unexpectedly suppressed CLP-induced IL-33 upregulation in the lungs. Thus, IL-33 levels after CLP are highly dependent on the mode of ventilation.



Eight- to 10-week-old male C57BL/6 mice were purchased from Jackson Laboratory. IL-33 knock-out (KO) and ST2 KO male mice were originally obtained from Nakae (19) and maintained in our animal facility. All mice used were on a C57BL/6 background with appropriate backcrossing for respective knockouts. Transgenic mice were confirmed to be the desired genotype via standard PCR-based techniques. Animal protocols were approved by the University of Pittsburgh Animal Care and Use Committee and experiments were performed in strict adherence to the National Institutes of Health Guidelines for the Use of Laboratory Animals. Mice were bred and housed in specific pathogen-free conditions with free access to food and water.


Anti-IL-33 (ab54385) and anti-beta actin (ab6276) were obtained from Abcam (Cambridge, Mass); anti-IL-33 (AF3626) came from R&D systems, Inc (Minneapolis, Minn); the mouse lung dissociation kit was purchased from Miltenyi Biotec; Fixable Viability Dye eFluor 506; antimouse CD45 PerCP-Cy5.5, antimouse CD11b FITC, and antimouse Ly6G (Gr-1) APC were obtained from eBioscience; Evans blue came from Sigma-Aldrich USA.

CLP followed by mechanical ventilation

Sepsis was induced by CLP as described (20). Mice weighing 25 g to 30 g were used. The mice were anesthetized via intraperitoneal (i.p.) administration of 100 mg/kg ketamine and 10 mg/kg xylazine. Skin was disinfected with 2% iodine tincture. Laparotomy was performed and 50% of the cecum was ligated and punctured twice with a 22-gauge needle. The cecum was then returned to the peritoneal cavity and the abdominal incision was closed with 4-0 sterile synthetic absorbable sutures. Saline (1 mL) was given subcutaneously (s.c.) for resuscitation immediately after the operation. For analgesia, buprenorphine (0.1 mg/kg, Butler Schein, Dublin, Ohio) was injected to mice s.c. 2 h after CLP. Mice were given antibiotics (PRIMAXIN, 25 mg/kg; Merck) s.c. after surgery. In some experiments, anesthetized mice were subjected to MTV (10 mL/kg) or LTV (6 mL/kg) 6 h after CLP. An i.p. injection of one-third the initial dose of ketamine and xylazine was administered every 30 min to maintain adequate anesthesia during MV. Body temperature was maintained at 37°C via a heating pad. Tracheotomy and intubation using an 18G catheter was performed. Subsequently, animals were connected to a Harvard Apparatus ventilator for 2 or 4 h. VT was set at 10 mL/kg and frequency was set at 150/min, zero positive end-expiratory pressure (PEEP) (moderate in the sense that it was slightly above the range of measured VT (7 mL/kg) and respiratory rate during spontaneous ventilation) or lung volume protective ventilation was set at 6 mL/kg and frequency was set at 200/min, zero PEEP. In some experiments, mice were intratracheally administered recombinant IL-33 (10 μg/mouse) using a MicroSpray syringe (MicroSprayer/Syringe Assembly for Mouse, MSA-250-M, Penn-Century, Inc, Wyndmoor, PA) before MV.

Western blot analysis

Lung tissues were lysed in buffer (Cell Signaling Technology) and phenylmethylsulfonyl fluoride. Protein concentrations were subsequently determined by standard bicinchoninic acid assay. After addition of 6 × sodium dodecyl sulfate (SDS) loading buffer, equivalent amounts of protein were heated (100°C; 5 min) and separated by gel electrophoresis using a 10% SDS-polyacrylamide electrophoresis gel. Resolved proteins were then transferred to a nitrocellulose membrane and blocked with Tris-buffered saline containing Tween-20 (TBST) and 5% nonfat milk (1 h; 24°C). Nitrocellulose membranes were incubated overnight at 4°C with primary antibody. The membranes were washed in TBST three times, incubated with horseradish peroxidase-conjugated secondary antibody for 1 h at 37°C, and then washed in TBST three additional times before being developed for chemiluminescence (Thermo Fisher Scientific). Western blots were quantitated using Quantity One software (Bio-Rad, Foster City, Calif) and normalized to β-actin signal.

Histological analysis

Lung tissue samples were fixed in 4% paraformaldehyde in phosphate buffered saline (PBS) overnight at 4°C. The samples were then dehydrated, embedded in paraffin, and cut into 5 μm sections. After deparaffinization, the tissues were stained with hematoxylin and eosin for histological analysis. Lung sections were scored for lung injury, including the following: alveolar and capillary edema; intravascular and peri-bronchial influx of inflammatory cells; thickness of the alveolar wall; and hemorrhage. The items were semiquantitatively scored as none, minimal, light, moderate, or severe (score 0, 1, 2, 3, or 4, respectively) by a pathologist blinded to the experimental group. The lung injury score was obtained by averaging the scores from the animals within each group.

Alveolar-capillary permeability measurements

To evaluate alveolar-capillary barrier function (21, 22), Evans blue albumin (EBA; 0.5%, 25 mg/kg body weight) was injected into the internal jugular vein 1 h before euthanasia and lung harvesting. Blood samples were obtained from the right heart and the pulmonary vasculature was subsequently infused with 1 mL PBS. The lung tissue was homogenized in 2 mL PBS and incubated with an additional 2 mL of formamide (Sigma-Aldrich) (18 h; 60°C). Formamide extracts were centrifuged (15,000 g × 30 min; 4°C) and the supernatants were collected to quantify lung EBA content using a dual-wavelength (620 nm and 740 nm) spectrophotometric method. Pulmonary EBA absorbance at 620 nm was corrected by a factor with EBA absorbance at 740 nm. The EBA permeability index was calculated by dividing pulmonary EBA absorbance at 620 nm/g of lung tissue by plasma EBA absorbance at 620 nm.


Plasma and lung homogenate were assayed for IL-33, ST2, cytokines (TNF-α, IL-6), and chemokines (MIP-2 and MCP-1) using commercially available ELISA reagents (Duoset; R&D System).


Data are presented as the means ± SEM of the indicated number of experiments and analyzed using analysis of variance; post hoc testing was performed using the Bonferroni modification of the t test. The individual studies performed throughout this work represent at least five independent studies. All statistical analyses were carried out using the GraphPad Prism 5 program. P values of less than 0.05 were considered statistically significant.


MTV increases and LTV suppresses lung levels of cytokines and chemokines in septic mice

To assess the impact of MTV and LTV on sepsis-induced lung injury, we developed a model in which CLP was followed 6 h later by ventilation using MTV (10 mL/kg, 150 breaths/min, room air 21% O2) or LTV (6 mL/kg, 200 breaths/min, room air 21% O2) for 2 or 4 h. Mice receiving the combination of CLP plus MV were compared with mice subjected to CLP alone for 8 and 10 h, or sham operation followed 6 h later by 2 or 4 h of MV. Lung homogenate levels of IL-6, TNF-α, MIP-2, and MCP-1 were measured at 8 and 10 h after CLP to assess the magnitude of the intrapulmonary inflammatory responses. These times were selected to coincide with the application of MV for 2 or 4 h after CLP for 6 h. CLP alone induced the expected increase in cytokines and chemokines, while MTV and LTV alone did not. However, when MTV was performed at 6 h after the onset of CLP, levels of all four mediators were seen to significantly rise above the levels measured with CLP alone (Fig. 1, A–D). In contrast, when LTV was performed at 6 h after the onset of CLP, levels of all four mediators were significantly lower than the levels measured with CLP alone (Fig. 2, A–D).

Fig. 1
Fig. 1:
Moderate tidal volume (MTV) ventilation increases lung levels of cytokines and chemokines in septic mice.
Fig. 2
Fig. 2:
Low tidal volume (LTV) ventilation decreases lung levels of cytokines and chemokines in septic mice.

MTV aggravates and LTV prevents CLP-induced lung damage

Next, lung injury was assessed at the 10 h time point. CLP alone led to modest lung injury as demonstrated by histology (Fig. 3B) and a significant increase in alveolar-capillary permeability (Fig. 3A) as measured by EBA dye leak into the lungs. MTV alone had no impact on lung injury or permeability, but when applied after CLP, markedly worsened both lung injury score and alveolar-capillary permeability. In striking contrast, LTV, which alone also induced no lung injury, significantly suppressed CLP-induced lung injury as demonstrated by a lower lung injury score (Fig. 3B) and improved barrier function compared with CLP alone (Fig. 3A).

Fig. 3
Fig. 3:
Moderate tidal volume (MTV) aggravates, but low tidal volume (LTV) improves CLP-induced lung damage.

MTV upregulates while LTV downregulates the IL-33-ST2 pathway in the lungs of septic mice

IL-33 signaling is activated by epithelial injury and has been shown to contribute to lung injury in endotoxemia. We have shown that IL-33 contributes to early lung injury in the CLP model (23) and we and others have shown that IL-33 is involved in VILI (17, 24). We postulated that MV during sepsis might induce stress or damage, leading to further IL-33 release. In wild-type mice, we noted that: MTV and LTV alone did not change the levels of IL-33 in the lung (Fig. 4, A–D) or levels of soluble ST2 in plasma (Fig. 4, E and F); CLP led to significant upregulation in both IL-33 and ST2; MTV after CLP led to a 1.5 to 2-fold increase in IL-33 (Fig. 4, A and C) and ST2 (Fig. 4E) over CLP alone; and remarkably, the level of IL-33 in the lungs (Fig. 4, B and D) and sST2 in plasma (Fig. 4E) were downregulated with LTV after CLP compared with CLP alone.

Fig. 4
Fig. 4:
Moderate tidal volume (MTV) upregulates, while low tidal volume (LTV) downregulates the IL-33-ST2 pathway in the lung of septic mice.

MTV-enhanced lung damage and inflammation during sepsis are dependent on the IL-33-ST2 pathway

To determine the role of the IL-33-ST2 pathway in MTV-enhanced CLP-induced lung damage and inflammation, IL-33 and ST2 KO male mice were subjected to the combination of CLP and MTV. Both lung injury score (Fig. 5A) and alveolar-capillary permeability (Fig. 5B) induced by CLP+MTV were attenuated significantly in IL-33−/− and ST2−/− mice. In addition, the levels of the cytokines (TNF-α and IL-6) (Fig. 6, A and B) and chemokines (MCP-1 and MIP-2) (Fig. 6, C and D) in lung homogenate were significantly lower in IL-33−/− and ST2−/− mice subjected to MTV+CLP compared with wild-type mice.

Fig. 5
Fig. 5:
Moderate tidal volume (MTV) enhances CLP-induced lung damage dependent on IL-33-ST2 pathway.
Fig. 6
Fig. 6:
Moderate tidal volume (MTV) enhances CLP-induced lung levels of cytokines and chemokines dependent on the IL-33-ST2 pathway.

Intratracheal rIL-33 reverses the protective effect of LTV on septic mice

The above results suggested that the level of IL-33 production was a determinant of the consequences of MV on sepsis-induced lung injury. We assessed this possibility by administering recombinant IL-33 (rIL-33, 10 μg/mouse) via the trachea at the onset of LTV in mice subjected to CLP. Recombinant IL-33 or PBS as a control were given just prior to LTV. As shown in Figure 7, administration of rIL-33 markedly increased, and hence reversed, the protective effects of LTV on lung injury score (Fig. 7A) and alveolar-capillary permeability (Fig. 7B) in wild-type mice receiving the combination of CLP and LTV compared with PBS controls. This change in lung injury with rIL-33 was accompanied in significant increases in lung levels of cytokines (IL-6, TNF-a) (Fig. 8, A and B) and chemokines (MCP-1, MIP-2) (Fig. 8, C and D) in mice subjected to CLP+LTV.

Fig. 7
Fig. 7:
rIL-33 intratracheally reverses the protective of low tidal volume (LTV) in CLP-induced lung damage.
Fig. 8
Fig. 8:
rIL-33 intratracheally reverses the protective function of low tidal volume (LTV) in CLP-induced lung levels of cytokines and chemokines.


MV with high or even moderate tidal volume can cause alveolar overstretching and VILI (25, 26). Lower tidal volume without PEEP or repeated recruitment maneuvers can promote atelectasis and alveolar decruitment, which also induce VILI (3). Lung-protective MV strategies include a more physiologic tidal volume with PEEP, and appropriate recruitment measures are protective in patients at risk for ARDS; however, a standardized strategy using lung-protective ventilation during surgery in patients as risk for ARDS has not been adopted (27, 28). Patients undergoing surgery for intra-abdominal sepsis are especially at risk for ALI. We show here that MTV after CLP dramatically increases lung injury and inflammation within 4 h and that this is IL-33- and ST2-dependent. LTV ventilation suppresses lung injury after CLP, and this is associated with lower lung IL-33 levels than those seen in mice subjected to CLP alone. These findings show that ventilation mode is a determinant of IL-33-ST2 signaling and show IL-33-ST2 signaling as a proximal driver of VILI in sepsis. Protective ventilation may prevent lung injury by suppressing IL-33 expression in the lung.

We used a two-hit mouse model (CLP followed by MTV or LTV) to study the role of the IL-33-ST2 pathway in lung injury associated with MV following sepsis. Patients suffering from intra-abdominal sepsis frequently require urgent surgery with MV. Thus, this model corresponds to the acute onset of sepsis due to gastrointestinal perforation followed by MV for oxygenation or delivery of anesthetics for intraoperative care seen in the clinical setting. Four hours of ventilation alone, whether MTV or LTV, did not impact the parameters used to measure lung injury or inflammation. However, the impacts of MTV and LTV on lung responses during sepsis were dramatically different with MTV increasing and LTV significantly reducing sepsis-induced lung injury and inflammation. Our recent work showing that IL-33 contributes to lung injury early after the onset of sepsis (23), along with reports showing that that ventilation induces IL-33 release (17) led us to hypothesize that the IL-33-ST2 pathway could be involved in the ventilation-induced changes in this model. Indeed, IL-33 and sST2 levels correlated with the degree of lung injury in the two-hit model. Furthermore, the increase in lung injury and inflammation induced by MTV following CLP were prevented by deletion of IL-33 or ST2.

MV leads to inflammation by altering cellular processes in the lung via mechanical forces; however, how mechanical forces are sensed by immune cells and converted into biochemical signals for intracellular signal transduction is unclear. Mechanical strain (rats at 10 cm H2O of inspiratory pressure for 4 h) can induce full-length IL-33 secretion in the absence of cellular necrosis (16, 24). Zhang et al. (29) found IL-33 pretreatment overall decreased the survival rate and aggravated lung inflammation and injury induced by intratracheal LPS. IL-33 is known to be important for activating neutrophils to clear bacteria from the peritoneum during CLP (30, 31) and we have shown that IL-33−/− mice have less lung injury and cellular infiltration within 6 h of CLP (23). Therefore, the increase in lung injury seen with MTV following CLP might be explained by the induction of IL-33 expression and release in response to mechanical stress. We have recently shown that IL-33 activates type 2 innate lymphoid cells (ILC2) to produce IL-5 in the lungs in both sepsis (23) and trauma (18). IL-33 may drive neutrophil influx and activation through IL-5 in CLP. It is possible that ILC2-dependent and -independent pathways account for the enhanced lung injury and inflammation observed in the two-hit model with MTV.

ST2 is the only established receptor for IL-33. There are two main ST2 isoforms, membrane-bound (ST2L) and soluble forms (sST2). sST2 is a soluble secreted protein consisting of the extracellular cytokine-binding domains. Soluble ST2 blocks IL-33 signaling due to its ability to trap IL-33 and prevent it from binding to ST2L on the surface of cells (32). Mice with loss of IL-33 nuclear localization signals or constitutive over-expression of IL-33 develop systemic inflammation that is abrogated by crossing onto the ST2-deficient background (33, 34).

We found that CLP with MTV increases sST2 levels in the plasma. Since IL-33 is also known to contribute to lung repair, it is possible that sST2 might block the protective effects of IL-33 and promote lung injury though this mechanism. While we cannot rule out this possibility, the demonstration that ST2−/− mice were also protected from enhanced lung injury in CLP+MTV suggests that ST2 signaling was required for IL-33-dependent lung injury and inflammation. IL-33 is known to be important for driving bacterial clearance in the CLP model through the recruitment and activation of neutrophils (30). We have speculated that an unwanted consequence of this adaptive response is lung injury, resulting in IL-33-driven overactivation of inflammatory pathways in the lung (18, 23). MTV appears to further promote this pathway in the early phases of sepsis.

The protective effects of LTV following CLP were partially reversed by the administration of rIL-33, supporting the conclusion that LTV protects against lung injury and inflammation, in part by reducing CLP-induced IL-33 upregulation. How LTV blocks IL-33 upregulation is uncertain. Although the exact mechanisms leading to VILI are unknown, compared with moderate ventilation settings, implementation of protective ventilation strategies in humans has been shown to decrease the development of ARDS and postoperative pulmonary complications. The degree of mechanotransduction that is the conversion of mechanical stimuli to a biochemical response when the alveolar epithelium or vascular endothelium is stretched during MV during sepsis might contribute to either a protective effect (e.g., LTV) or an injurious effect (e.g., MTV) on the lung at risk.

An important limitation of our work is that we did not get the results about mechanical ventilation on physical signs of sepsis mice, such as the oxygen index (PaO2/FiO2), mean arterial pressure, and blood gas analysis. Because of the limitation of total blood volume in mice, it is difficult to repeatedly measure arterial blood gas throughout the experiment. However, we have to admit internal environment stability is a crucial factor. In this experiment, we found that LTV inhibits IL33 secretion and thus protects the sepsis-induced lung injury. However, unfortunately we still do not know how the cell recognizes the mechanical signal of LTV, which translates into a chemical signal that reduced IL33 secretion. In future experiments, we will continue to explore this issue.


In summary, we provide evidence that the IL-33-ST2 pathway plays a dominant role in the lung injury that is observed when MTV is used within the first 6 h following the onset of sepsis. The strong induction of IL-33 by MTV and conversely, the suppression of IL-33 by LTV, further confirm that IL-33 expression and signaling is very much dependent on the degree of mechanical stretch. Our results support the use of protective ventilation strategies when MV is required for the management of intra-abdominal sepsis.


The authors thank Ms Christine Heiner, Scientific Writer for the Departments of Anesthesiology and Surgery at the University of Pittsburgh School of Medicine, for assisting with scientific editing of the manuscript.


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IL-33; low tidal volume; mechanical ventilation; moderate tidal volume; sepsis; ST2

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