Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury

Abstract

Previous studies have shown that heat shock protein 72 (Hsp72) is found in the extracellular space (eHsp72) and that eHsp72 has potent immunomodulatory effects. However, whether eHsp72 is present in the distal air spaces and whether eHsp72 could modulate removal of alveolar edema is unknown. The first objective was to determine whether Hsp72 is released within air spaces and whether Hsp72 levels in pulmonary edema fluid would correlate with the capacity of the alveolar epithelium to remove alveolar edema fluid in patients with ALI/ARDS. Patients with hydrostatic edema served as controls. The second objective was to determine whether activation of the stress protein response (SPR) caused the release of Hsp72 into the extracellular space in vivo and in vitro and to determine whether SPR activation and/or eHsp72 itself would prevent the IL-1β-mediated inhibition of the vectorial fluid transport across alveolar type II cells. We found that eHsp72 was present in plasma and pulmonary edema fluid of ALI patients and that eHsp72 was significantly higher in pulmonary edema fluid from patients with preserved alveolar epithelial fluid clearance. Furthermore, SPR activation in vivo in mice and in vitro in lung endothelial, epithelial, and macrophage cells caused intracellular expression and extracellular release of Hsp72. Finally, SPR activation, but not eHsp72 itself, prevented the decrease in alveolar epithelial ion transport induced by exposure to IL-1β. Thus SPR may protect the alveolar epithelium against oxidative stress associated with experimental ALI, and eHsp72 may serve as a marker of SPR activation in the distal air spaces of patients with ALI.Keywords pulmonary edema; alveolar fluid clearance; heat shock response; respiratory distress syndrome; heat shock protein 70 ACUTE LUNG INJURY (ALI) is a common cause of acute respiratory failure in critically ill patients. The early phase of ALI is characterized by the accumulation and activation of inflammatory cells (neutrophils and macrophages) within the distal air spaces that release high levels of oxidant species (46). Alveolar epithelial and lung endothelial injury leads to increased permeability, Copyright © 2006 the American Physiological SocietyAddress for reprint requests and other correspondence: M. T. Ganter, Dept. of Anesthesia and Perioperative Care, San Francisco General Hospital, 1001 Potrero Ave., Rm. San Francisco, CA 94110 (mt.ganter@gmail.com).. NIH Public AccessAuthor Manuscript Am J Physiol Lung Cell Mol Physiol. Author manuscript; available in PMC 2009 October 21. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript pulmonary edema, and acute respiratory failure. An important mechanism to prevent alveolar flooding is the maintenance or upregulation of lung alveolar fluid clearance (AFC), requiring an intact alveolar epithelium (47). However, AFC has been shown to be impaired in the majority of ALI patients, and an impaired AFC was associated with worse clinical outcomes (47).Heat shock or stress proteins (Hsp) are a ...

Hsp72 Induces Inflammation and Regulates Cytokine Production in Airway Epithelium through a TLR4- and NF-κB-Dependent Mechanism

“…3 Patients with hydrostatic pulmonary edema had Hsp72 levels of 160 Ϯ 51 ng/ml in the bronchoalveolar lavage fluid (BALF) vs 603 Ϯ 153 ng/ml in patients with ALI. Additionally, in this cohort, patients with impaired alveolar fluid clearance had lower levels of Hsp72 in the edema fluid (25). These results suggest that the presence of adequate levels of Hsp72 in the airways is associated with improved alveolar fluid clearance and may be protective in the setting of ALI.…”

“…Other investigators have identified Hsp72 levels of 160 Ϯ 51 ng/ml in the BALF of patients with hydrostatic pulmonary edema vs 603 Ϯ 153 ng/ml in patients with ALI (25). Our initial mouse inhalation experiments were performed using 100 ng and 1 g of Hsp72 per inhalation.…”

“…Although these studies suggest that increased levels of extracellular Hsp72 are associated with a poor prognosis, others have found improved outcomes in those patients with more elevated levels of extracellular Hsp72 (24,25). For example, Ganter et al (25) recently reported an increase in the levels of Hsp72 in the pulmonary edema fluid of patients with acute lung injury (ALI). 3 Patients with hydrostatic pulmonary edema had Hsp72 levels of 160 Ϯ 51 ng/ml in the bronchoalveolar lavage fluid (BALF) vs 603 Ϯ 153 ng/ml in patients with ALI.…”

Hsp-72, a candidate prognostic indicator of heatstroke

“…These could have accounted for the differential Hsp-72 expression noted in our study. Until recently, heat shock proteins were considered intracellular proteins, however, the detection of Hsp-60 and Hsp-72 in the sera of normal individuals (Pockley et al 1999;Pockley et al 2002) and observations of increased circulating levels of Hsp-72 in various conditions such as cardiovascular (Wright et al 2000;(Dybdahl et al 2005), acute lung injury (Ganter et al 2006), heat illness (Wu et al 2001), and trauma (Wright et al 2000;Wu et al 2001;Pittet et al 2002;Pockley et al 2002) raised the question of a potential extracellular role. In classical heatstroke, two clinical studies so far have reported high circulating levels of Hsp-72 and Hsp-60 with conflicting findings (Wang et al 2001;Huisse et al, 2008).…”

Association of heat shock protein 70 expression with rat myocardial cell damage during heat stress in vitro and in vivo

“…The heat shock proteins (Hsps) are a set of proteins synthesized in response to physical, chemical, or biological stresses, including heat exposure (McCormick et al, 2003;Ganter et al, 2006;Staib et al, 2007). Hsps are the most broadly distributed class of proteins and are also among the most highly conserved proteins in nature.…”