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.

Fig. 1

(a–h, j) Representation of histological appearances (H&E stained) for lung tissue samples collected in this study. All these samples were representative of the spectrum of changes in ARDS, showing a clear disease progression from early stage leading to the end-stage lung fibrosis. The morphological description of these samples is shown in Table 1.

Fig. 2

The characterization of the list of 107 genes studied.

Fig. 3

Expression profiles of the top 5 genes that are significantly up-regulated in the severity progression of SARS-CoV infections (open bars represent early disease stage samples; filled bars represent late disease stage samples).

Fig. 4

Expression profiles of the top 5 genes that are significantly down-regulated in the severity progression of SARS-CoV infections (open bars represent early disease stage samples; filled bars represent late disease stage samples).

Fig. 5

List of genes involved in immunological response against viral or bacterial infection (data were analyzed through the use of Ingenuity^® Pathway Analysis).

Fig. 6

The IHC results demonstrated the correlation between gene and protein expression profiles in SARS-CoV infected patients.

Fig. 7

Hypothesized pathogenesis model for SARS-CoV infections.