Elevated lnterleukin-1 Release by Human Alveolar Macrophages during the Adult Respiratory Distress Syndrome

Jacobs, R F; Tabor, Dale R.; Burks, A. Wesley; Campbell, G. Douglas

doi:10.1164/ajrccm/140.6.1686

Cited by 160 publications

(76 citation statements)

References 14 publications

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“…In the lung, alveolar macrophages produce excessive amounts of IL-1b in patients with ARDS (27). Chemical and biological inhibition of the IL-1 pathway has improved indices of VILI in animal models (28,29), but most patients with ARDS did not benefit from IL-1 receptor antagonist treatment (30).…”

Section: Discussionmentioning

confidence: 99%

Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

Dolinay

Kim

Howrylak

et al. 2012

Am J Respir Crit Care Med

485

424

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Rationale: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation. Objectives: We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. Methods: We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid. Measurements and Main Results: In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality. Conclusions: The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.

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Section: Discussionmentioning

confidence: 99%

Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

Dolinay

Kim

Howrylak

et al. 2012

Am J Respir Crit Care Med

485

424

View full text Add to dashboard Cite

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“…Dysregulation of IL-1␤ processing and release is linked with severe clinical disease, such as sepsis, acute respiratory distress syndrome, rheumatoid arthritis, and overwhelming infection (3)(4)(5)(6)(7)51). Also, IL-18, another proinflammatory cytokine activated by ICE, is involved in numerous diseases, such as sepsis, myocardial suppression, collagen-induced arthritis, inflammatory bowel disease, and hepatic injury (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

“…2). However, overproduction of IL-1␤ can produce the features of septic shock, including hypotension, capillary leak, and acute respiratory distress syndrome (3)(4)(5). Conversely, underproduction of IL-1␤ can predispose to overwhelming infection and death (6,7).…”

mentioning

confidence: 99%

Janus Kinase 3 Down-Regulates Lipopolysaccharide-Induced IL-1β-Converting Enzyme Activation by Autocrine IL-10

Kim

Hart

Knatz

et al. 2004

The Journal of Immunology

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ProIL-1β processing by IL-1β-converting enzyme (ICE) and the subsequent release of mature IL-1β are highly regulated events in the monocyte/macrophage response to pathogens. This process occurs in a controlled way through the activation of the constitutively expressed 45-kDa ICE precursor (proICE). To characterize the signaling pathways involved in ICE regulation in human monocytes/macrophages, we analyzed ICE activation in the presence of specific inhibitors of classic signaling pathways. Although LPS-induced ICE activity was not significantly affected by interruption of extracellular signal-regulated kinase, p38 kinase, or phosphoinositol 3-kinase, Janus kinase 3 (JAK3) inhibition produced a significant dose-dependent enhancement of LPS-induced ICE activity. Support for the inhibitory role of JAK3 was shown by the fact that IL-4 (which uses JAK1 and JAK3 signaling) suppressed LPS-induced ICE activity and by the finding that JAK3 knockout macrophages have increased LPS-induced ICE activation. To understand how JAK3 down-regulates LPS-induced ICE activity in monocytes, we hypothesized that JAK3 signaling enhances IL-10 production. In support of this model we show that LPS-induced IL-10 expression was synchronous with ICE deactivation, IL-4 induced the release of IL-10, exogenous IL-10 suppressed LPS-induced ICE activity, a neutralizing IL-10 Ab increased LPS-induced ICE activity, and, finally, JAK3 knockout macrophages displayed significantly reduced LPS-induced IL-10 production. These findings support a model in which JAK3 signaling enhances IL-10 production leading to down-regulation of ICE activation and suppression of IL-1β processing and release.

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“…The pathogenesis of adult respiratory distress syndrome (ARDS) is largely unknown, and the mortality remains well in excess 50% [6]. Among all, Alveolar acrophages (AMs) play a pivotal role in the pathogenesis of ARDS.…”

mentioning

confidence: 99%

“…Inducible nitric oxide synthase (iNOS) is the enzyme produced by monocytes and macrophages which is responsible for the generation of a large amount of nitric oxide (NO). Excessive production of NO by iNOS for long periods may be cytotoxic and cytostatic to pulmonary cells in rodents [6]. However, the expression of iNOS in human pulmonary macrophages remains controversial [7,15].…”

mentioning

confidence: 99%