Vascular Permeability and Ocular Infections

描述（由申请方提供）：眼内炎是一种由于将微生物引入眼后段而导致的威胁视力的眼内感染。严重的眼内炎通常导致视网膜脆弱细胞的不可逆损伤和爆炸性眼内炎症，最终导致视力丧失。尽管积极的抗生素，抗炎和手术治疗，显着的视力（如果不是眼睛本身）可以在短时间内丧失。治疗失败的规律性突出了对针对疾病致病机制的更好治疗的需要。目前的治疗方法可以对眼睛进行消毒，但无法限制破坏性炎症，并且忽略了同样具有破坏性的细菌产物。 我们的研究主要集中在创伤后眼内炎（PTE）的致病机制，最近，在克雷伯氏菌和葡萄球菌内源性眼内炎（EE）的新模型。我们已经确定了一个共同的主题眼内炎引起的这些和其他病原体：视网膜血管通透性是一个初始的和重要的组成部分，疾病的过程。这项新的建议集中在细菌性眼内炎演变的非常早期阶段的血管渗透性，当生物体进入眼睛并引发炎症时。我们假设在PTE和术后（POE）细菌性眼内炎中触发的血管通透性促进炎性细胞流入眼后段（目的1）。我们同样假设，全身性感染期间开始的血管通透性促进微生物进入眼睛，导致EE（目的2）。在这些类型的眼内炎中，结果是感染、炎症和潜在的视力丧失。在这些不同类型的眼内炎中，视网膜血管通透性导致细胞和细菌进入眼睛的潜在机制尚不清楚。然而，如果这些事件包括可识别的共同因素，可以作为治疗目标，感染和炎症可能会受到限制，从而保护视力。 待测试的目标是建立在我们的细菌PTE/POE模型和细菌EE新模型中的已发表和新数据的基础上，目的是破译眼内炎期间视网膜血管通透性的机制。目前的治疗没有考虑眼屏障完整性的变化，这可能是PTE/POE炎症和EE感染的前兆事件。我们和其他小组发表的眼内炎研究没有关注明显炎症之前眼内细菌识别的非常早期阶段， 这是一个关键的时刻，可以通过治疗来避免造成破坏性炎症的级联反应。因此，本提案的结果将提供有关眼内感染期间眼屏障防御的重要和临床相关信息，并确定潜在的治疗干预靶点，以防止疾病的破坏性和致盲作用。

DESCRIPTION (provided by applicant): Endophthalmitis is a sight-threatening infection of the interior of the eye resulting from the introduction of organisms into the posterior segment. Severe endophthalmitis often results in irreversible damage to delicate cells of the retina and explosive intraocular inflammation, ultimately resulting in vision loss. Despite aggressive antibiotic, anti-inflammatory, and surgical treatment, significant vision (if not the eye itself) cn be lost in a short period of time. The regularity of treatment failures highlights the need for beter therapeutics which target the pathogenic mechanisms of disease. Current treatments can sterilize the eye, but fail at limiting damaging inflammation and ignore bacterial products which can be equally as damaging. Our research has focused on the pathogenic mechanisms of Bacillus post-traumatic endophthalmitis (PTE) and, more recently, on new models of Klebsiella and Staphylococcus endogenous endophthalmitis (EE). We have identified a theme common to endophthalmitis caused by these and other pathogens: retinal vascular permeability is an initial and important component of the disease process. This new proposal focuses on vascular permeability during the very early stages in the evolution of bacterial endophthalmitis, when organisms enter the eye and inflammation is initiated. We hypothesize that vascular permeability triggered in PTE and post-operative (POE) bacterial endophthalmitis facilitates influx of inflammatory cells into the posterior segment (Aim 1). We similarly hypothesize that vascular permeability initiated during systemic infection facilitates the entry of organisms into te eye, resulting in EE (Aim 2). In these types of endophthalmitis, the outcome is infection, inflammation, and the potential for vision loss. The underlying mechanisms of retinal vascular permeability leading to cellular and bacterial access into the eye during these different types of endophthalmitis are not clear. However, if these events include identifiable common factors that can be therapeutically targeted, infection and inflammation could be limited, resulting in preservation of vision. The aims to be tested are built upon published and new data in our models of bacterial PTE/POE and new models of bacterial EE, with the goal of deciphering the mechanisms of retinal vascular permeability during endophthalmitis. Current therapies do not consider changes in ocular barrier integrity, a likely precursor event to inflammation in PTE/POE and infection in EE. Published studies on endophthalmitis by us and other groups have not focused on the very early stages of bacterial recognition in the eye prior to overt inflammation, a critical time when the cascades responsible for damaging inflammation could be therapeutically averted. Therefore, the findings from this proposal will provide important and clinically relevant information regarding ocular barrier defense during intraocular infection and identify potential targets for therapeutic intervention that will prevent devastating and blinding effects of the disease.