急性肺損傷 (acute lung injury, ALI) 和較為嚴重的急性呼吸窘迫症 (acute respiratory distress syndrome, ARDS) 為肺部劇烈的發炎反應所引起，病理上可以發現肺組織有瀰漫性肺上皮損傷，肺水腫和大量的嗜中性球 (neutrophil) 浸潤。許多證據顯示，調控嗜中性球的存活可以影響急性肺損傷病人的預後。譬如，抑制嗜中性球的凋亡和凋亡細胞的移除可以加重急性肺損傷的嚴重程度，而病人的肺泡沖洗液 (bronchoalveolar lavage fluid, BALF)中的促發炎細胞激素 (cytokines) 或趨化激素 (chemokines) 則能夠延緩嗜中性球的凋亡。這些肺泡沖洗液的發炎性物質被認為與病人的多器官衰竭有關。因此，這些發炎性物質對急性肺損傷的病人可能具有預後的價值。神經鞘脂質 (sphingolipid) 為細胞膜的組成成分，目前知道其對於細胞生長、存活和死亡亦具有調控的角色。其中神經醯胺 (ceramide) 可由神經鞘磷脂 (sphingomyelin) 經酸性或中性神經鞘磷脂酶 (acid or neutral sphingomyelinase, aSMase or nSMase) 代謝產生，具有次級訊息傳遞者的功能。一旦細胞受到了外在的刺激，例如促發炎細胞激素和內毒素(lipopolysaccharide, LPS)，所產生的 ceramide 會增強發炎反應並導致細胞凋亡。Ceramide 的代謝產物 sphingosine-1-phosphate (S1P)，則相反地具有抑制細胞凋亡的功能。S1P可以媒介不同激酶 (kinases) 和磷酸酶 (phosphatases) 的作用，例如 p38 mitogen-activated protein kinase (MAPK)，其功能與嗜中性白血球的黏附 (adhesion)、趨化 (chemotaxis)、tumor necrosis factor-α 和 CXC 趨化激素的合成、以及細胞凋亡的調控有關。在本研究中，我們探討肺泡沖洗液中的發炎性物質是否可以成為感染所造成的急性呼吸窘迫症病人的預後因子，以及研究細胞內 sphingolipid 是否會抑制嗜中性球的凋亡而促進急性肺損傷的發生。結果發現急性呼吸窘迫症病人的肺泡沖洗液中的發炎性物質與病人病情的嚴重度和預後有關，其中以 IL-8 為預測死亡最重要的因子。然後我們研究嗜中性球在有無給予抑制劑的情況下，以內毒素抑制凋亡程度是否有所不同。我們發現內毒素抑制嗜中性球凋亡的能力會因加入 nSMase 抑制劑 sphingolactone-24 (Sph-24)、sphingosine kinase 抑制劑 sphingosine kinase inhibitor (SKI)-II、和 p38 MAPK 抑制劑 SB203580而被阻斷，但 aSMase 抑制劑則無此作用。同樣地，給予 Sph-24 和 SKI-II 也會抑制內毒素所引起的 p38 MAPK 磷酸化。接著我們進一步利用內毒素引發急性肺損傷的小鼠模式，評估給予 nSMase 抑制劑 Sph-24 對於肺損傷的嚴重程度和存活率的影響。我們發現施予 Sph-24 治療的小鼠可以降低內毒素所引起的急性肺損傷的嚴重性和增加存活率。我們同樣也觀察到急性呼吸窘迫症病人的肺泡嗜中性球 ceramide 和 phospho-p38 MAPK 的表現量比心因性肺水腫的病人來得高。總而言之，我們證明了急性呼吸窘迫症病人的肺泡沖洗液中的發炎性物質可以用來預測病人的預後；此外，活化嗜中性球的 nSMase/S1P 路徑可以使 p38 MAPK 磷酸化，導致細胞凋亡被抑制，進而促使急性肺損傷的形成。

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are characterized by overwhelming lung inflammation which reveals a diffuse damage of lung epithelium, edema formation, and the massive infiltration of neutrophils. Accumulating evidence has shown that regulation of neutrophil survival is related to the outcome in ALI patients. For example, inhibition of neutrophil apoptosis or the clearance of apoptotic neutrophils appear to be deleterious in ALI, and the proinflammatory cytokines and chemokines contained in bronchoalveolar lavage fluids (BALF) from patients with ALI prevent neutrophils from apoptosis. The inflammatory mediators in BALF have been proposed to contribute to the development of multiple organ dysfunctions in ALI patients. Therefore, determination of the inflammatory mediators in BALF might be of prognostic relevance. Sphingolipids are the components of plasma membrane and known to play essential role in cell growth, survival, and death. Ceramide, generated from sphingomyelin through acid or neutral sphingomyelinase (aSMase or nSMase), acts as a second messenger in response to various stimuli, such as proinflammatory cytokines and lipopolysaccharide (LPS), resulting in the amplification of inflammatory response and the induction of apoptosis. In contrast, its further metabolite, sphingosine-1-phosphate (S1P), has been recognized to function as a survival signal. S1P mediates the activation of various intracellular kinases and phosphatases, such as p38 mitogen-activated protein kinase (MAPK), which modulates neutrophil adhesion, chemotaxis, synthesis of tumor necrosis factor-α and CXC chemokines, and apoptosis. In this study, we explored the inflammatory mediators in BALF for prognostic relevance in patients with infection-induced ARDS and tested the hypothesis that sphingolipids would attenuate neutrophil apoptosis which contributes to the development of ALI. We found that several mediators in BALF from ARDS patients are correlated with clinical severity and outcome, in particular, IL-8 is the most significant predictor for mortality. Furthermore, LPS-stimulated human neutrophils, with or without inhibitor treatment, were analyzed for apoptosis. We found that the inhibitory effect of LPS on neutrophil apoptosis was blocked by treatment with the nSMase inhibitor sphingolactone-24 (Sph-24), sphingosine kinase inhibitor (SKI)-II, and p38 MAPK inhibitor SB203580, but not by the aSMase inhibitor chlorpromazine. LPS-activated phosphorylation of p38 MAPK was attenuated by treatment with Sph-24 and SKI-II. Moreover, mice with LPS-induced lung injury were treated with the nSMase inhibitor Sph-24 to evaluate its impact on lung injury and survival. The severity of LPS-induced ALI was reduced and the survival rate was increased in mice treated with Sph-24 compared with that in those given LPS alone. Intracellular levels of sphingolipids in alveolar neutrophils from patients with ARDS were also measured. We found that intracellular levels of ceramide and phospho-p38 MAPK were elevated in alveolar neutrophils from ARDS patients. Our results demonstrate that inflammatory mediators in BALF are predictive for the severity and outcome of patients with ARDS, and activation of the nSMase/S1P pathway to induce p38 MAPK phosphorylation results in inhibition of neutrophil apoptosis, which may contribute to the development of ALI.

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