Pulmonary fibrosis (PF) is a progressive and lethal lung disease of elderly whose incidence has been increasing following the Covid-19 pandemic caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). PF immunopathogenesis involves progressive alveolar epithelial cell damage, release of damage-associated molecular patterns (DAMPs), and extracellular matrix (ECM) injury. We assessed the dynamic role of LMW-hyaluronan (LMW-HA) as DAMP in initiation of host immune TLR-2,4 responses and as determinant in progression of ECM injury to fibrosis. Male Wistar rats were divided into Group I (saline control, n = 24) and Group II (intratracheal bleomycin, 7 U/kg/animal, n = 24). Animals were euthanized on 0, 7, 14, and 28 days. The time course of release of LMW-HA, TLR-2,4 mRNA and protein levels, and NF-κB-p65 levels after bleomycin injury were correlated with the development of parenchymal inflammation, remodelling, and fibrosis. Acute lung injury caused by bleomycin significantly increases the pro-inflammatory LMW-HA levels and elevates TLR-2,4 levels on day 7. Subsequently, TLR-2 upregulation, TLR-4 downregulation, and NF-κB signalling follow on days 14 and 28. This results in progressive tissue inflammation, alveolar and interstitial macrophage accumulation, and fibrosis. LMW-HA significantly increases in PF caused by non-infectious and infectious (Covid-19) etiologies. The accumulating HA fragments function as endogenous DAMPs and trigger inflammatory responses, through differential TLR2 and TLR4 signalling, thus promoting inflammation and macrophage influx. LMW-HA are reflective of the state of ongoing tissue inflammation and may be considered as a natural biosensor for fibrotic lung diseases and as potential therapeutic targets.

中文翻译：

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LMW-透明质酸片段和Toll样受体2,4在博来霉素诱导的肺实质性纤维化损伤进展中的动态作用

肺纤维化（PF）是一种老年人的进行性致死性肺部疾病，在严重的急性呼吸系统综合症冠状病毒2（SARS-CoV-2）导致Covid-19大流行之后，其发病率一直在增加。PF免疫发病机制包括进行性肺泡上皮细胞损伤，损伤相关分子模式（DAMP）释放和细胞外基质（ECM）损伤。我们评估了LMW-透明质酸（LMW-HA）作为DAMP在宿主免疫TLR-2,4应答的启动中的动态作用以及在ECM纤维化损伤进展中的决定性作用。将雄性Wistar大鼠分为I组（盐水对照，n ＝ 24）和II组（气管内博来霉素，7U / kg /动物，n ＝ 24）。在第0、7、14和28天对动物实施安乐死。LMW-HA，TLR-2,4 mRNA和蛋白质水平释放的时间过程，博来霉素损伤后的NF-κB-p65和NF-κB-p65水平与实质炎症，重塑和纤维化的发展有关。博来霉素引起的急性肺损伤在第7天显着增加了促炎性LMW-HA的水平，并升高了TLR-2,4的水平。随后，在第14天和之后出现了TLR-2上调，TLR-4下调和NF-κB信号传导。 28.这导致进行性组织炎症，肺泡和间质巨噬细胞蓄积以及纤维化。由非感染性和感染性（Covid-19）病因引起的LMW-HA PF显着增加。积累的HA片段起内源性DAMP的作用，并通过不同的TLR2和TLR4信号转导触发炎症反应，从而促进炎症和巨噬细胞流入。