The Association Between BMI and Plasma Cytokine Levels in Patients With Acute Lung Injury

doi:10.1378/chest.10-0014

Chest

Volume 138, Issue 3, September 2010, Pages 568-577

https://doi.org/10.1378/chest.10-0014 Get rights and content

Background

Obesity is associated with poor outcomes in many diseases, although recent data suggest that acute lung injury (ALI) is an exception. This is particularly interesting because obesity is marked by increased levels of proinflammatory mediators associated with increased morbidity and mortality in ALI. We hypothesized that cytokine response might be attenuated in patients who are obese and critically ill or that obesity might modify the relationship between plasma cytokines and clinical outcomes in ALI.

Methods

We analyzed plasma biomarker levels (interleukin [IL]-6, IL-8, tumor necrosis factor-α receptor 1, surfactant protein D [SP-D], soluble intracellular adhesion molecule, von Willebrand factor (vWF), protein C, and plasminogen activator inhibitor-1) collected at baseline and day 3 in 1,409 participants in prior National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network (ARDSNet) trials. BMI was calculated for each patient, and associations with cytokine levels and ventilator-free days (VFDs), organ failure-free days (OFDs), and mortality were investigated in regression models adjusting for confounders.

Results

In adjusted analyses, plasma IL-6 (P = .052), IL-8 (P = .001), and SP-D (P < .001) were inversely related to BMI, whereas vWF (P = .001) and WBC count (P = .042) increased proportionally with BMI. BMI was not associated with increased morbidity or mortality and did not modify the association between baseline biomarker levels and mortality, VFDs, or OFDs.

Conclusions

Patients who are obese and have ALI have lower levels of several proinflammatory cytokines, suggesting that the inflammatory response may be altered in patients with ALI and a high BMI. Lower SP-D but higher vWF suggests decreased epithelial and increased endothelial injury in the lung of patients who are obese. Mechanisms by which obesity may modulate innate immunity in critical illness are unclear, and future studies should elucidate such mechanisms.

Section snippets

Patient Selection

We examined data from patients who participated in four randomized controlled trials (RCTs) conducted by the NHLBI ARDSNet.23, 24, 25, 26 Of the 1,451 patients in these four studies, 861 participated in the RCT of mechanical ventilation comparing lower tidal volume with higher tidal volume (6 mL/kg of predicted body weight vs 12 mL/kg).²³ This RCT was conducted simultaneously with two other clinical trials in which ketoconazole or lisofylline were compared with placebo in a factorial design.25,

Baseline Characteristics

The 42 patients that we excluded because of lack of either height or weight measurement, when compared with the 1,409 included patients, had lower severity of illness at admission (APACHE III score 75.8 ± 27.1 vs 87.6 ± 30.4, P = .01), had less diabetes (2.4% vs 17.5%, P = .02), and had more trauma (28.6% vs 9.2%, P < .001) and less sepsis (9.5% vs 25.0%, P = .03) as their ALI risk factor. Among the study population, we did not find a significant difference in age between BMI groups, but we did

Discussion

Individuals who are obese but otherwise healthy have elevated levels of proinflammatory cytokines relative to individuals who are healthy and of normal weight. In the obese state, adipose tissue is a metabolically active tissue consisting of adipocytes with infiltrating macrophages that produce a variety of mediators thought to be related to many of the metabolic consequences of obesity.19, 37 These cytokines include many of the proinflammatory mediators associated with worse outcomes in

Conclusions

In summary, we have found that increasing BMI is associated with both decreasing plasma inflammatory biomarkers and increasing WBC count, but not with a change in mortality, in patients who are critically ill with ALI. These findings suggest that innate immunity could be altered in patients who are obese. However, the mechanisms by which obesity may modulate innate immunity in critical illness are not clear. Future studies are needed to understand how obesity may alter the inflammatory response

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Acute lung injury (ALI) is a serious illness that develops suddenly, progresses rapidly, has a poor treatment response and a high mortality rate. Studies have found that circular RNAs (circRNA) play a critical role in several diseases, but their role in ALI remains unclear. The aim of this study was to identify circRNAs that are associated with ALI and investigate their potential molecular mechanisms. A comparison of lung circRNA and microRNA expression profiles in mice with ALI and controls was performed by RNA-sequencing. A bioinformatic analysis was conducted to identify differentially expressed (DE) RNAs, to construct competitive endogenous RNA (ceRNA) networks, and to analyze their function and pathways. Then, a protein-protein interaction (PPI) network was generated by the Search Tool for the Retrieval of Interacting Genes database, and hub genes were identified using Cytoscape. Furthermore, a key ceRNA subnetwork was constructed based on these hub genes. Overall, we found 239 DE circRNAs and 42 DE microRNAs in ALI mice compared to controls. Additionally, the molecular mechanism of ALI was further understood by building ceRNA networks based on these DE genes. ALI-induced circRNAs are mostly function in the inflammatory response and metabolic processes. Moreover, DE circRNAs are primarily involved in the nuclear factor (NF)-kappa B and PI3K-Akt signaling pathways. Seven hub genes were derived from the PPI network of 191 genes, followed by the construction of circRNA-miRNA-hub gene subnetworks. In this study, circRNA profiles are remarkably changed in mice with LPS-triggered ALI, and their potential contribution to the disease is revealed.
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The development of ALI is closely related to the apoptosis of alveolar epithelial cells, resulting in functional impairment of the alveolar epithelial barrier (Zheng et al., 2020). ALI is a serious disease with sudden onset, rapid progression, poor treatment response and high mortality (Stapleton et al., 2010; Villar et al., 2011). Therefore, it is of great clinical significance to study the pathogenesis of ALI and find new drug targets.
This study aimed to investigate the promoting effect of acid-sensing ion channel 1a (ASIC1a) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and its mechanisms. Methods: In this experiment, the ALI rat model was induced by intratracheal injection of LPS, and the ASIC1a specific blocker psalmotoxin-1 (PcTx-1) was injected into the tail vein before LPS administration once. Western blot, immunofluorescence, immunohistochemistry and real-time PCR methods were used to detect ASIC1a and apoptosis-related proteins expressions in lung tissue and RLE-6TN rat type II alveolar epithelial cells. Confocal Laser Scanning Microscopy was used to detect Ca²⁺ fluorescence intensity in RLE-6TN cells. Results: PcTx-1 pretreatment not only inhibited the pathological changes of LPS-induced ALI in lung tissue, but also inhibited lung dysfunction. PcTx-1 also reduced the increased levels of the apoptosis-related proteins B-cell lymphoma-2-associated X (Bax) and cleaved cysteinyl aspartate specific proteinase 3 (Cleaved caspase-3) and increased the decreased level of B-cell lymphoma-2 (Bcl-2) in the lung tissue of the model group. LPS-induced changes in mitochondrial membrane potential and calcium influx in alveolar epithelial cells were also reversed by PcTx-1. Conclusion: ASIC1a induces an apoptotic response in ALI through mitochondrial apoptosis.
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Our systematic review did not reveal any association between PICU admission BMI status and outcomes in critically ill children. Further investigation with standardized nutrition status classification on admission, stratified by patient subgroups, is needed to clarify the association between nutritional status and clinical outcomes of PICU patients.
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Funding/Support: This research was partially supported by the National Institutes of Health [Grants HL084200, P20 RR015557, HL081332, and NO1HR46064].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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Chest

Original ResearchCritical Care MedicineThe Association Between BMI and Plasma Cytokine Levels in Patients With Acute Lung Injury

Background

Methods

Results

Conclusions

Section snippets

Patient Selection

Baseline Characteristics

Discussion

Conclusions

Pharmacol Ther

Atherosclerosis

Surgery

Chest

Chest

Chest

Chest

Diabetes Res Clin Pract

Chest

Thromb Res

Lancet Infect Dis

Adipose tissue, insulin action and vascular disease: inflammatory signals

Int J Obes Relat Metab Disord

C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?

Arterioscler Thromb Vasc Biol

Is visceral adiposity the “enemy within”?

Arterioscler Thromb Vasc Biol

Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes

Diabetologia

The acute respiratory distress syndrome

N Engl J Med

Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury

Crit Care Med

Interleukin-8 in sepsis: relation to shock and inflammatory mediators

Infect Immun

Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome

Ann Intern Med

Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome

Crit Care Med

Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury

Am J Respir Crit Care Med

Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury

Thorax

Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders

Crit Care Med

von Willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injury

Crit Care Med

Original Research
Critical Care Medicine
The Association Between BMI and Plasma Cytokine Levels in Patients With Acute Lung Injury