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Herpes virus infection is associated with vascular remodeling and pulmonary hypertension in idiopathic pulmonary fibrosis.

Calabrese F, Kipar A, Lunardi F, Balestro E, Perissinotto E, Rossi E, Nannini N, Marulli G, Stewart JP, Rea F - PLoS ONE (2013)

Bottom Line: The influence of viruses on PH associated with IPF is unknown.A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected.The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy. fiorella.calabrese@unipd.it

ABSTRACT

Background: Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed.

Methods: Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice.

Results: A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p = 0.01), poorer performance in the six minute walking test (6MWT; p = 0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p = 0.002 and p = 0.004) and higher TGF-β expression (p = 0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p = 0.03), poorer performance in the 6MWT (p = 0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients.

Conclusion: Herpesviral infections may contribute to the development of PH in IPF patients.

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Related in: MedlinePlus

In situ hybridization for EBV.EBER transcripts well seen in the nuclei of two alveolar epithelial cells (arrows). Bar scale: 10 µm.
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pone-0055715-g001: In situ hybridization for EBV.EBER transcripts well seen in the nuclei of two alveolar epithelial cells (arrows). Bar scale: 10 µm.

Mentions: Patients with IPF showed a higher frequency of viral infection than control cases (40% vs 7.3%; p = 0.0003). Normal lungs were all negative. Herpes viruses were the only detected genomes in IPF and EBV resulted as the most frequent, present in more than half of IPF patients. In 2 cases double infection was found. EBV was never detected in control cases (DPLDs and normal lungs). Gene sequencing of all amplicons showed a high homology (from 95% to 99%) with human viral genome sequences. RNA-ISH for EBV (EBER) identified viral RNA in 40% of EBV-PCR positive IPF cases. The positivity was detected in alveolar epithelial cells other than within monocytes/macrophages (Figure 1). Real time PCR showed a high number of EBV genome copies (mean±SD:1085000±120208 copies/µl DNA). The extent of fibrosis in IPF lungs showed a mean of 36.7±12.3% (range: 14.6%–65.3%) and was significantly higher than in the DPLD control group (36.7±12.3% vs 15.4±15.4%, p<0.0001). Normal lungs from donors showed no evidence of pathological remodelling.


Herpes virus infection is associated with vascular remodeling and pulmonary hypertension in idiopathic pulmonary fibrosis.

Calabrese F, Kipar A, Lunardi F, Balestro E, Perissinotto E, Rossi E, Nannini N, Marulli G, Stewart JP, Rea F - PLoS ONE (2013)

In situ hybridization for EBV.EBER transcripts well seen in the nuclei of two alveolar epithelial cells (arrows). Bar scale: 10 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585298&req=5

pone-0055715-g001: In situ hybridization for EBV.EBER transcripts well seen in the nuclei of two alveolar epithelial cells (arrows). Bar scale: 10 µm.
Mentions: Patients with IPF showed a higher frequency of viral infection than control cases (40% vs 7.3%; p = 0.0003). Normal lungs were all negative. Herpes viruses were the only detected genomes in IPF and EBV resulted as the most frequent, present in more than half of IPF patients. In 2 cases double infection was found. EBV was never detected in control cases (DPLDs and normal lungs). Gene sequencing of all amplicons showed a high homology (from 95% to 99%) with human viral genome sequences. RNA-ISH for EBV (EBER) identified viral RNA in 40% of EBV-PCR positive IPF cases. The positivity was detected in alveolar epithelial cells other than within monocytes/macrophages (Figure 1). Real time PCR showed a high number of EBV genome copies (mean±SD:1085000±120208 copies/µl DNA). The extent of fibrosis in IPF lungs showed a mean of 36.7±12.3% (range: 14.6%–65.3%) and was significantly higher than in the DPLD control group (36.7±12.3% vs 15.4±15.4%, p<0.0001). Normal lungs from donors showed no evidence of pathological remodelling.

Bottom Line: The influence of viruses on PH associated with IPF is unknown.A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected.The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy. fiorella.calabrese@unipd.it

ABSTRACT

Background: Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed.

Methods: Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice.

Results: A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p = 0.01), poorer performance in the six minute walking test (6MWT; p = 0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p = 0.002 and p = 0.004) and higher TGF-β expression (p = 0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p = 0.03), poorer performance in the 6MWT (p = 0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients.

Conclusion: Herpesviral infections may contribute to the development of PH in IPF patients.

Show MeSH
Related in: MedlinePlus