Limits...
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.

Show MeSH

Related in: MedlinePlus

TGF-β expression in IPF lung tissue.A) Significantly increased TGF-β median score values of epithelial cells are seen in virus positive cases. B) TGF-β median score values of macrophages in virus positive and virus negative cases. Stronger and more extensive TGF-β immunostaining well seen in virus positive (C) than virus negative case (D). Bar scale: 5 µm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585298&req=5

pone-0055715-g005: TGF-β expression in IPF lung tissue.A) Significantly increased TGF-β median score values of epithelial cells are seen in virus positive cases. B) TGF-β median score values of macrophages in virus positive and virus negative cases. Stronger and more extensive TGF-β immunostaining well seen in virus positive (C) than virus negative case (D). Bar scale: 5 µm.

Mentions: Virus positive IPF cases showed a higher total thickening of muscular arteries (50.3%, 43.8–58.8% vs 39.5%, 34.7–45.7%, p = 0.002) than virus negative cases. The intimal layer was most severely affected (21.8%, 17.2–26.8% vs 15.5%, 12.6–19.1%; p = 0.004) (Figure 3 A,B,C,D). TUNEL staining was mainly detected in the endothelial cells of the microvasculature (Figure S1) while cell proliferation was frequently seen in remodelled pulmonary arteries. Strong Ki-67 positivity was observed in both endothelial cells (CD31 positive, data not shown) and smooth muscle cells (smooth muscle actin positive, data not shown). Vessel cell proliferation was particularly seen in pulmonary arteries in proximity to metaplastic alveolar epithelial cells or macrophages (Figure 4 A and B). TGF-β scores were higher in virus-positive cases, although this was only statistically significant when epithelial expression was considered (score: 195, 140–210 vs 100, 40–120; p = 0.002) (Figure 5 A,B,C,D). The statistical value of these parameters (vessel remodelling and TGF-β expression) was still evident when EBV positive IPF patients were compared with both other virus positive and negative IPF cases (p<0.05 for all). A summary of all main clinicopathological features in relation to virus infection among IPF patients is shown in the Table S1.


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)

TGF-β expression in IPF lung tissue.A) Significantly increased TGF-β median score values of epithelial cells are seen in virus positive cases. B) TGF-β median score values of macrophages in virus positive and virus negative cases. Stronger and more extensive TGF-β immunostaining well seen in virus positive (C) than virus negative case (D). Bar scale: 5 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0055715-g005: TGF-β expression in IPF lung tissue.A) Significantly increased TGF-β median score values of epithelial cells are seen in virus positive cases. B) TGF-β median score values of macrophages in virus positive and virus negative cases. Stronger and more extensive TGF-β immunostaining well seen in virus positive (C) than virus negative case (D). Bar scale: 5 µm.
Mentions: Virus positive IPF cases showed a higher total thickening of muscular arteries (50.3%, 43.8–58.8% vs 39.5%, 34.7–45.7%, p = 0.002) than virus negative cases. The intimal layer was most severely affected (21.8%, 17.2–26.8% vs 15.5%, 12.6–19.1%; p = 0.004) (Figure 3 A,B,C,D). TUNEL staining was mainly detected in the endothelial cells of the microvasculature (Figure S1) while cell proliferation was frequently seen in remodelled pulmonary arteries. Strong Ki-67 positivity was observed in both endothelial cells (CD31 positive, data not shown) and smooth muscle cells (smooth muscle actin positive, data not shown). Vessel cell proliferation was particularly seen in pulmonary arteries in proximity to metaplastic alveolar epithelial cells or macrophages (Figure 4 A and B). TGF-β scores were higher in virus-positive cases, although this was only statistically significant when epithelial expression was considered (score: 195, 140–210 vs 100, 40–120; p = 0.002) (Figure 5 A,B,C,D). The statistical value of these parameters (vessel remodelling and TGF-β expression) was still evident when EBV positive IPF patients were compared with both other virus positive and negative IPF cases (p<0.05 for all). A summary of all main clinicopathological features in relation to virus infection among IPF patients is shown in the Table S1.

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