key: cord-0033570-wuvq788p
authors: Iwasaka, Hideo
title: Three-step research strategies for ARDS: new target molecules—ACE2, HMGB1, and HSP47
date: 2007-01-30
journal: J Anesth
DOI: 10.1007/s00540-006-0475-9
sha: 03a8349c41d9afd5dccf4a856a94d08792789149
doc_id: 33570
cord_uid: wuvq788p

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Angiotensin-converting enzyme 2 (ACE2), which has recently been identifi ed as a negative regulator of the renin-angiotensin (RA) system and as a potential receptor for severe acute respiratory syndrome (SARS) virus, is expressed in lungs [1] . ACE2 negatively regulates the RA system by inactivating angiotensin II. The activated RA system promotes the pathogenesis of lung edemas and impairs lung function in the acute phase of ARDS. I tried using an angiotensin II receptor type 1 (AT1) antagonist for the purpose of inactivating the RA system in an endotoxin-treated rat model. The AT1 antagonist improved the histological lung edema and protected against the downregulation of ACE2 in lung tissue.

High mobility group box 1 (HMGB1), in addition to its role as a transcriptional regulatory factor, has recently been identifi ed as a late mediator of endotoxin lethality [2] . HMGB1 has been demonstrated to be a longsearched-for nuclear danger signal that is passively released by necrotic, as opposed to apoptotic, cells that will induce infl ammation. Lipopolysaccharide (LPS)induced acute lung injury was almost completely resolved by treatment with two antibodies [that for HMGB1 and its receptor, receptor for advanced glycation endproducts (RAGE)] and the use of a newly developed extracorporeal column, an "HMGB1 absorber". These results demonstrate that the specifi c inhibition and absorption of endogenous HMGB1 therapeutically reverses the lethality of established sepsis-induced lung injury, indicating that HMGB1 inhibitors and this absorber could be used in a clinically relevant therapeutic The acute respiratory distress syndrome (ARDS) is a common, devastating clinical syndrome of acute lung injury that affects both medical and surgical patients. This syndrome is often progressive, and is characterized by distinct stages with different clinical, histopathological, and radiographic manifestations. I consider that these stages consist of three different phases, an acute and exudative phase, an exacerbatory infl ammatory phase, and the last phase, fi brosing alveolitis. An improved understanding of the pathogenesis of ARDS has led to the assessment of several novel treatment strategies. Therefore, I believe that we have to investigate the strategies that hasten the resolution of ARDS according to the three different phases.

window that is signifi cantly wider than that for other known cytokines.

Heat shock protein (HSP)47 is a procollagen/collagen specifi c molecular chaperone protein and essential for the early stages of collagen biosynthesis [3] . The formation of collagenous fi brous tissue is a vital part of the process of fi brosing alveolitis. The expression of HSP47 has been reported to increase in parallel with the expression of collagens during the progression of various fi brosis models. We attempted to attenuate pulmonary collagen accumulation by inhibiting the overexpression of HSP47 with antisense oligonucleotides in an experimental pulmonary fi brosis model induced with bleomycin. The administration of HSP47 antisense oligonucleotides markedly suppressed the increased production of collagens and attenuated the histologic manifestations of the disease.

Like any form of infl ammation, acute lung injury and ARDS represent a complex process in which multiple pathways can propagate or inhibit the lung injury. The most common risk factor for ARDS was reported to be severe sepsis with a suspected pulmonary source, followed by severe sepsis with a suspected nonpulmonary source. Infl ammation itself can migrate to various or-gans as do spreading cancer cells. Therefore, improving our understanding of the pathogenesis of ARDS and devising new strategies for treating ARDS in the exacerbatory phase are important, because almost all ARDS patients are admitted to intensive care units during this period. In this period, infl ammation can be exacerbated not only by infective organisms but also by endogenous proteins released from injured tissues. We call this the pernicious infl ammatory cycle of infl ammatory autoinjury (see Fig. 1 ).

The above three-step research strategies used from the onset of lung injury to the end-stage of ARDS have led to the assessment of novel clinical treatment strategies. Fig. 1 . The concept of infl ammatory autoinjury is shown as a pernicious infl ammatory cycle. After the onset of infl ammation, injured tissue releases endogenous intracellular proteins, such as HMGB1 and several HSPs, which work as immune disruptors. These proteins interact with toll-like receptors, which activate the infl ammatory response. ROS, radical oxygen species; HMGB1, high mobility group box 1; HSP, soluble heat shock protein; TLRs, toll-like receptors

Angiotensin-converting enzyme 2 protects from severe acute lung failure

HMG-1 as a late mediator of endotoxin lethality in mice

Characterization of a novel transformation-sensitive heat-shock protein (HSP47) that binds to collagen