Impact of HIV infection on α1-antitrypsin in the lung - PubMed (original) (raw)

Impact of HIV infection on α1-antitrypsin in the lung

Sarah E Stephenson et al. Am J Physiol Lung Cell Mol Physiol. 2018.

Abstract

Emphysema is one of the most common lung diseases in HIV+ individuals. The pathogenesis of HIV-associated emphysema remains unclear; however, radiographic distribution and earlier age of presentation of emphysema in the lungs of HIV+ patients are similar to deficiency of α1-antitrypsin (A1AT), a key elastase inhibitor in the lung. Reduced levels of circulating A1AT in HIV+ patients suggest a potential mechanism for emphysema development. In the present study we asked if A1AT levels and activity in the bronchoalveolar lavage fluid (BALF) differ in HIV+ and HIV- patients with and without emphysema. A1AT levels were measured by ELISA in plasma and BALF from a cohort of 21 HIV+ and 29 HIV- patients with or without emphysematous changes on chest CT scan. To analyze A1AT function, we measured elastase activity in the BALF and assessed oxidation and polymerization of A1AT by Western blotting. Total A1AT was increased in the BALF, but not in the plasma, of HIV+ compared with HIV- patients, regardless of the presence or absence of emphysema. However, antielastase activity was decreased in BALF from HIV+ patients, suggesting impaired A1AT function. Higher levels of the oxidized form of A1AT were detected in BALF from HIV+ than HIV- patients, which may account for the decreased antielastase activity. These findings suggest that, in the lungs of HIV+ patients, posttranslational modifications of A1AT produce a "functional deficiency" of this critical elastase inhibitor, which may contribute to emphysema development.

Keywords: HIV; emphysema; α1-antitrypsin.

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Figures

Fig. 1.

Circulating and local α1-antitrypsin (A1AT) levels. A_–_D: total A1AT in bronchoalveolar fluid (BALF; A and C) and A1AT concentration in plasma (B and D) of HIV+ and HIV− patients. E: A1AT expression in monocyte-derived macrophages (MDMs, n = 7) and peripheral blood lymphocytes (PBLs, n = 3) at 7 days post-HIV infection. Values are medians ± interquartile range (IQR); each point represents an individual patient or donor. P values were calculated using the Mann-Whitney _U_-test (A and B) or 1-way ANOVA with Tukey’s post test (C and D).

Fig. 2.

BALF and plasma elastase activity. A: schematic outlining experimental design. _N_-Succ-Ala-pNA, _N_-succinyl-Ala-Ala-Ala-_p_-nitroanilide; OD, optical density. B and C: elastase activity in BALF and plasma of HIV+ and HIV− patients. D and E: elastase activity in BALF and plasma by HIV and emphysema status. Values are medians ± IQR; n = 12 for HIV− without emphysema and HIV+ with emphysema, n = 9 for HIV+ without emphysema, n = 17 for HIV− with emphysema. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, by 2-way ANOVA with Bonferroni’s post test.

Fig. 3.

BALF elastase levels based on HIV (A) and emphysema (B) status. Each point represents an individual patient; widest line indicates median ± IQR.

Fig. 4.

Oxidation of A1AT in BALF and plasma. A: representative blot of oxidized A1AT (ox-A1AT) from BALF using an antibody specific for ox-A1AT; 2 ng of ox-A1AT were loaded as positive control. B: densitometry of ox-A1AT Western blots of BALF samples. C: representative blot of ox-A1AT from plasma using an antibody specific for oxidized A1AT; 50 ng of ox-A1AT were loaded as positive control. D: densitometry of ox-A1AT Western blots of plasma samples. Each point represents an individual patient; line indicates median; n = 9 for HIV+ normal, n = 17 for HIV− with emphysema, n = 12 for HIV+ with emphysema.

Fig. 5.

Polymerized A1AT (poly-A1AT) in BALF. A: representative Western blot of poly-A1AT from BALF. B and C: densitometry of poly-A1AT Western blots by HIV and emphysema status. Each point represents an individual patient; line indicates median; n = 12 for HIV− normal and HIV+ with emphysema, n = 9 for HIV+ normal, n = 17 for HIV− with emphysema.

Fig. 6.

Proinflammatory cytokine concentrations in BALF. Proinflammatory cytokine levels were measured in BALF by multiplex analysis. A and B: granulocyte colony-stimulating factor; C and D: chemokine (C-X-C motif) ligand 1 (CXCL1); E and F: IL-8. Each point represents an individual patient; widest bar indicates median of the group ± IQR. P values were calculated using the Mann-Whitney _U_-test (A, C, and E) or 1-way ANOVA with Tukey’s post test (B, D, and F).

Fig. 7.

Summary of proposed model.

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Impact of HIV infection on α1-antitrypsin in the lung - PubMed (original) (raw)