Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients

Abstract

Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury. It is a response to various diseases of variable etiology, including SARS-CoV infection. To date, a comprehensive study of the genomic physiopathology of ARDS (and SARS) is lacking, primarily due to the difficulty of finding suitable materials to study the disease process at a tissue level (instead of blood, sputa or swaps). Hereby we attempt to provide such study by analyzing autopsy lung samples from patient who died of SARS and showed different degrees of severity of the pulmonary involvement. We performed real-time quantitative PCR analysis of 107 genes with functional roles in inflammation, coagulation, fibrosis and apoptosis; some key genes were confirmed at a protein expression level by immunohistochemistry and correlated to the degree of morphological severity present in the individual samples analyzed. Significant expression levels were identified for ANPEP (a receptor for CoV), as well as inhibition of the STAT1 pathway, IFNs production and CXCL10 (a T-cell recruiter). Other genes unassociated to date with ARDS/SARS include C1Qb, C5R1, CASP3, CASP9, CD14, CD68, FGF7, HLA-DRA, IGF1, IRF3, MALAT-1, MSR1, NFIL3, SLPI, USP33, CLC, GBP1 and TAC1. As a result, we proposed to therapeutically target some of these genes with compounds such as ANPEP inhibitors, SLPI and dexamethasone. Ultimately, this study may serve as a model for future, tissue-based analyses of fibroinflammatory conditions affecting the lung.

Differential expression of lncRNAs during the HIV replication cycle: an underestimated layer in the HIV-host interplay

“…Nonetheless, these overlapping mRNAs and lncRNAs validate our experimental setup and form ideal targets to be further investigated in the context of HIV infection. For instance, a well-known and characterized lncRNA, MALAT1 (lnc-SCYL1-1) is found in both datasets and is already linked to viral infection43. In addition, in HIV infected individuals MALAT1 is shown as a potential biomarker44.…”

SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon

“…Consistent with ARDS progression, the primary targets of SARS-CoV infection are ciliated cells of the airway epithelium and alveolar Type II pneumocytes [12,13]. ARDS is also associated with the induction of inflammatory cytokines including IL-1, IL-6, IL-8, CXCL-10, and TNFa, many of which were highly expressed in the lungs of SARS patients [14,15]. In many viral infections the antiviral cytokine Interferon (IFN) acts not only to control viral infections, but also to program the adaptive immune response to promote viral clearance [16].…”

Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS‐CoV, MERS‐CoV, and 2019‐nCoV

“…Therefore, the clinical deterioration of SARS-CoV infection may result from a combination of direct virus-induced cytopathic effects and immunopathology induced by a hyper-cytokinemia or a "cytokine-storm." Studies of the changes in cytokine/chemokine profiles during SARS-CoV infection revealed increased levels of circulating cytokines, such as tumor necrosis factor α (TNF-α), CXCL-10, interleukin-6 (IL-6), and IL-8, likelycontributed to the poor prognosis in SARS-CoV infections 15. …”