Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, Rotterdam, The Netherlands
Antimicrob Agents Chemother. 2017 Dec 21;62(1). doi: 10.1128/AAC.00960-17. Print 2018 Jan.
Host chitinases, chitotriosidase and acidic mammalian chitinase (AMCase), improved the antifungal activity of caspofungin (CAS) against These chitinases are not constitutively expressed in the lung. Here, we investigated whether chitosan derivatives were able to induce chitinase activity in the lungs of neutropenic rats and, if so, whether these chitinases were able to prolong survival of rats with invasive pulmonary aspergillosis (IPA) or of rats with IPA and treated with CAS. An oligosaccharide-lactate chitosan (OLC) derivative was instilled in the left lung of neutropenic rats to induce chitotriosidase and AMCase activities. Rats instilled with OLC or with phosphate-buffered saline (PBS) were subsequently infected with and then treated with suboptimal doses of CAS. Survival, histopathology, and galactomannan indexes were determined. Instillation of OLC resulted in chitotriosidase and AMCase activities. However, instillation of OLC did not prolong rat survival when rats were subsequently challenged with In 5 of 7 rats instilled with OLC, the fungal foci in the lungs were smaller than those in rats instilled with PBS. Instillation of OLC did not significantly enhance the survival of neutropenic rats challenged with and treated with a suboptimal dosage of CAS. Chitotriosidase and AMCase activities can be induced with OLC, but the presence of active chitinases in the lung did not prevent the development of IPA or significantly enhance the therapeutic outcome of CAS treatment.
宿主几丁质酶、壳三糖苷酶和酸性哺乳动物几丁质酶（AMCase）提高了棘白菌素（CAS）对 的抗真菌活性。这些几丁质酶在肺部不是组成型表达的。在这里，我们研究了壳聚糖衍生物是否能够诱导中性粒细胞减少症大鼠肺部的几丁质酶活性，如果是这样，这些几丁质酶是否能够延长侵袭性肺曲霉病（IPA）大鼠或接受 CAS 治疗的 IPA 大鼠的存活时间。将一种寡糖-乳酸壳聚糖（OLC）衍生物注入中性粒细胞减少症大鼠的左肺以诱导壳三糖苷酶和 AMCase 活性。用 OLC 或磷酸盐缓冲盐水（PBS）注入的大鼠随后感染 ，然后用亚最佳剂量的 CAS 治疗。确定了存活率、组织病理学和半乳甘露聚糖指数。OLC 的注入导致了壳三糖苷酶和 AMCase 活性的产生。然而，当大鼠随后受到 的挑战时，OLC 的注入并没有延长大鼠的存活时间。在 7 只注入 OLC 的大鼠中，有 5 只肺部的真菌病灶比注入 PBS 的大鼠小。在中性粒细胞减少症大鼠中，用亚最佳剂量的 CAS 治疗后，注入 OLC 并没有显著提高其存活率。OLC 可以诱导壳三糖苷酶和 AMCase 活性，但肺中活性几丁质酶的存在并不能阻止 IPA 的发展，也不能显著提高 CAS 治疗的疗效。
