Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome

Abstract

Background Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction and can sometimes lead to a highly aggressive form of pulmonary fibrosis that mimics the fatal lung condition called idiopathic pulmonary fibrosis (IPF). Although the activities of various matrix metalloproteinases (MMPs) are known to be dysregulated in IPF, it remains to be determined whether similar changes in these enzymes can be detected in HPS. Results Here, we show that transcript and protein levels as well as enzymatic activities of MMP-2 and -9 are markedly increased in the lungs of mice carrying the HPS Ap3b1 gene mutation. Moreover, immunohistochemical staining localized this increase in MMP expression to the distal pulmonary epithelium, and shRNA knockdown of the Ap3b1 gene in cultured lung epithelial cells resulted in a similar upregulation in MMP-2 and -9 expression. Mechanistically, we found that upregulation in MMP expression associated with increased activity of the serine/threonine kinase Akt, and pharmacological inhibition of this enzyme resulted in a dramatic suppression of MMP expression in Ap3b1 deficient lung epithelial cells. Similarly, levels and activity of different MMPs were also found to be increased in the lungs of mice carrying the Bloc3 HPS gene mutation and in the bronchoalveolar lavage fluid of subjects with HPS. However, an association between MMP activity and disease severity was not detected in these individuals. Conclusions In summary, our findings indicate that MMP activity is dysregulated in the HPS lung, suggesting a role for these proteases as biological markers or pathogenic players in HPS lung disease. Electronic supplementary material The online version of this article (10.1186/s13023-019-1143-0) contains supplementary material, which is available to authorized users.

Contributions of alveolar epithelial cell quality control to pulmonary fibrosis

“…These HPS AT2 models elaborate proinflammatory cytokines (e.g., MCP-1), complementing HPS mouse models that demonstrate AT2-mediated recruitment of profibrotic monocyte/macrophage lineages (73). In addition, AT2 cells were recently shown to serve as a source of both the profibrotic cytokine IL-11 (71,74,75) and matrix metalloproteinases (76).…”

Dissecting the novel mechanism of reduning injection in treating Coronavirus Disease 2019 (COVID-19) based on network pharmacology and experimental verification

“…Besides, matrix metalloproteinase (MMP) family members, including MMP2, MMP9, MMP12, MMP13, MMP1 and MMP8, also have higher degree values. MMPs play prominent roles in pulmonary inflammation and remodeling and have recently emerged as promising novel therapeutic targets in lung disease ( Summer, et al, 2019 ; Golestani, et al, 2017 ; Cui, et al, 2017 ). Most of the MMPs promote (rather than inhibit) the development of pulmonary fibrosis, and for patients who developed COVID-19 the main symptoms of them were pneumonia and fibrosis in the later stage ( Craig, et al, 2015 ; Wu et al, 2020 ).…”

Hermansky–Pudlak syndrome pulmonary fibrosis: a rare inherited interstitial lung disease

“…These findings indicate that peripheral blood fibrocyte concentration is associated with clinical outcome and suggest that fibrocytes may have a role in the pathobiology of disease. In addition, alterations in levels and activity of matrix metalloproteases in HPS may have a role in dysregulated turnover of extracellular matrix protein in the lung [80].…”