Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by an excessive inflammatory response involving a variety of inflammatory mediators, are associated with high morbidity and mortality in intensive care medicine

نویسندگان

  • JUN LIU
  • PENG - SHU ZHANG
  • QING YU
  • LING LIU
  • YI YANG
  • FENG - MEI GUO
  • HAI - BO QIU
چکیده

Acute lung injury (ALI) remains one of major causes of morbidity and mortality in intensive care medicine. The lack of efficient pharmacological interventions contributes to the high mortality rate of ALI. Losartan, an antagonist of angiotensin II (Ang II) type 1 receptor, is a potent therapeutic drug for ALI. Recent reports suggest that losartan inhibits the maturation of dendritic cells (DCs), impairs T-helper (Th) 1 immune response and ultimately attenuates inflammation in several Ang II-mediated inflammatory diseases. However, the possible protective mechanisms of losartan in ALI remain poorly understood. This study was aimed to define the effect of losartan on the frequency and phenotype of respiratory conventional DCs (cDCs) and Th cells polarization in lipopolysaccharide (LPS)-induced ALI mice. Results demonstrate that early after induction of LPS-induced ALI, cDCs expressing modest amounts of CD80 rapidly accumulated in the lungs. In addition, polarized Th1 and Th17 responses were markedly increased in LPS-induced ALI mice at 24 and 48 h. Of note, losartan led to inhibition of respiratory cDCs maturation at 6 h and suppressed Th1 and Th17 polarization responses compared with ALI mice at 24 and 48 h. Collectively, our findings may provide a novel and, at least, partial explanation for the protective effects by which losartan inhibits lung cDCs maturation and suppresses Th1 and Th17 immune responses. Introduction Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by an excessive inflammatory response involving a variety of inflammatory mediators, are associated with high morbidity and mortality in intensive care medicine (1). Over the past several decades, many pharmacological interventions for these entities have been evaluated, but none has clearly been shown to decrease mortality. Searching for effective therapeutic drugs is still urgently needed. Most recently, much attention has been focused on the involvement of the renin-angiotensin system (RAS) in the pathogenesis of ALI. In particular, our laboratory and others have demonstrated that angiotensin II (Ang II), as the major effector molecule of the RAS, is significantly increased in lung tissues and plays a key pro-inflammatory role in several ALI animal models (2-5). Losartan, an antagonist of Ang II type 1 receptor, is a potent therapeutic drug for ALI (2,5). However, the protective mechanisms of losartan in ALI remain poorly understood. The pattern of immune response in ALI is incompletely characterized. Dendritic cells (DCs), including conventional DCs (cDCs) and plasmacytoid DCs (pDCs), are crucial for the priming phase of the immune response (6). DCs are widely distributed in mucosal surfaces, including the lung (7). Indeed, DCs are thought to participate in a number of inflammatory lung diseases in both humans and mice (asthma, pulmonary infections, chronic obstructive pulmonary disease) (7-9). Most recently, a study has observed that mature DCs are markedly increased in the lung and play a key pro-inflammatory role in bleomycin-induced lung injury mice (10). Therefore, control of DCs function may be critical for strategies to modulate the lung inflammatory response. T-helper (Th) cells are known to play a significant role in the initiation of immune responses by providing help to other cells, which could at least be divided into subsets: Th1, Th2 and Th17 (6,11). Two recent clinical observations have shown that severe H1N1 influenza with ARDS is characterized by early secretion of Th1 and Th17 cytokines (12,13). These cytokine profiles have been previously reported to participate in both pro-inflammatory and antiviral responses. However, the exact role of Th cells in the ALI model merits further investigation. Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury JUN LIU, PENG-SHU ZHANG, QING YU, LING LIU, YI YANG, FENG-MEI GUO and HAI-BO QIU Department of Critical Care Medicine, Nanjing Zhong-Da Hospital, Southeast University School of Medicine, Nanjing 210009, P.R. China Received August 18, 2011; Accepted September 28, 2011 DOI: 10.3892/ijmm.2011.818 Correspondence to: Professor Hai-Bo Qiu, Department of Critical Care Medicine, Nanjing Zhong-Da Hospital, Southeast University School of Medicine, 87 Dingjiaqiao Road, Nanjing 210009, P.R. China E-mail: haiboq2000@yahoo.com.cn Abbreviations: ALI, acute lung injury; Ang II, angiotensin II; ARDS, acute respiratory distress syndrome; cDCs, conventional dendritic cells; DCs, dendritic cells; FCM, flow cytometry; i.t., intratracheal instillation; LPS, lipopolysaccharide; mDC, myeloid dendritic cell; pDC, plasmacytoid DC

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تاریخ انتشار 2011