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HIV is associated with an increased risk for emphysema. Matrix metalloproteinase 9 (MMP-9) is a lung tissue remodeling enzyme associated with emphysema. We previously found MMP-9 activity increases with increases in oxidative stress and that HIV increases alveolar oxidative stress. We hypothesized that HIV proteins would increase the risk of cigarette smoke-induced emphysema due to MMP-9.HIV-1 transgenic rats and wild-type littermates were exposed to cigarette smoke or sham for 8 weeks. Lung compliance and histology were assessed. Bronchoalveolar lavage (BAL), primary alveolar macrophages (AM), and serum samples were obtained. A rat alveolar macrophage cell line was exposed to the HIV protein Tat and MMP-9 levels were assessed by Western immunoblotting. MMP-9 protein expression and activity were assessed in AM from the HIV rat model by ELISA and cytoimmunofluoresence respectively. Serum from human subjects with and without HIV and tobacco dependence were assessed for MMP-9 levels.MMP-9 expression was significantly increased in rat alveolar macrophages after Tat exposure. HIV-1 transgenic rats developed emphysema while wild-type littermates did not. MMP-9 expression was also increased in the serum, BAL, and AM of HIV-1 transgenic rats after exposure to cigarette smoke compared to wild-type rats. In parallel, serum samples from HIV+ smokers had higher levels of MMP-9 than subjects without HIV and those who did not smoke.The combination of HIV and cigarette smoke increases MMP-9 expression in experimental rat HIV models and human subjects. HIV and cigarette smoke both induce alveolar oxidative stress and thereby increase MMP-9 activity.

Alcohol impairs pulmonary innate immune function and is associated with an increased risk of tuberculosis (TB). Toll-like receptor 2 (TLR2) is a pattern recognition receptor on alveolar macrophages that recognizes Mycobacterium tuberculosis (Mtb). The expression of TLR2 depends, in part, on granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. Given our prior work demonstrating the suppression of GM-CSF signaling following chronic alcohol ingestion, we hypothesized that alcohol impairs TLR2 expression via the suppression of GM-CSF and thereby reduces the ability of the macrophage to recognize and phagocytose Mtb.Primary alveolar macrophages were isolated from control-fed and alcohol-fed rats. Prior to cell isolation, some alcohol-fed rats were treated with intranasal GM-CSF and then endotracheally inoculated with an attenuated strain of Mtb. Primary macrophages were then isolated and immunofluorescence was used to determine phagocytic efficiency and TLR2 expression in the presence and absence of GM-CSF treatment and phagocytic efficiency in the presence and absence of TLR2 neutralization.TLR2 expression and phagocytosis of Mtb were significantly lower in the alveolar macrophages of alcohol-fed rats than control-fed rats. In parallel, blocking TLR2 signaling recapitulated this decreased phagocytosis of Mtb. In contrast, intranasal GM-CSF treatment restored TLR2 expression and Mtb phagocytosis in the alveolar macrophages of alcohol-fed rats to levels comparable to those of control-fed rats.Chronic alcohol ingestion reduces TLR2 protein expression and phagocytosis of Mtb, likely due to impaired GM-CSF signaling. GM-CSF restores membrane-bound TLR2 expression and phagocytic function.

Despite widespread use of antiretroviral therapy (ART), people with HIV (PWH) continue to suffer substantial morbidity and mortality from pulmonary diseases. We sought to evaluate the prevalence of pulmonary symptoms, evaluations, and diagnoses (both infectious and noninfectious) among PWH receiving care at one of the largest HIV clinics in the United States. All PWH seen at the Infectious Disease Program in Atlanta, Georgia, from July 2013 to June 2018 were included. Multivariable logistic regression was used to assess the odds of all-cause mortality. Among 8387 patients, median age was 48 years, 35% had documented smoking, 74% were male, and the 47% with ≥1 pulmonary symptom or diagnosis were older and had higher rates of smoking compared to those without any symptoms or diagnoses (p-values

Despite the advent of antiretroviral therapy, people living with HIV suffer from a range of infectious and noninfectious pulmonary complications. HIV impairs antioxidant defenses and innate immune function of the alveolar macrophage by diminishing granulocyte macrophage-colony stimulating factor (GM-CSF) signaling. Since GM-CSF may be linked to mitochondria, we sought to determine the effects of HIV on GM-CSF receptor expression and alveolar macrophage mitochondrial function. At an academic medical center, studies were completed on alveolar macrophages isolated from both wild-type and HIV transgenic (HIV Tg) rats and human subjects with and without HIV. Primary macrophages were plated and evaluated for expression of GM-CSF receptor beta, phagocytic index, and mitochondrial function in the presence and absence of GM-CSF treatment. GM-CSF receptor expression and mitochondrial function were impaired in macrophages isolated from HIV Tg rats, and treatment with GM-CSF restored GM-CSF receptor expression and mitochondrial function. GM-CSF treatment of HIV Tg rats also increased alveolar macrophage levels of the mitochondrial proteins voltage-dependent anion-selective channel 1 (VDAC) and glucose-regulated protein 75 (Grp75). Similar to the HIV Tg rat model, impairments in mitochondrial bioenergetics were confirmed in alveolar macrophages isolated from human subjects with HIV. HIV-associated impairments in alveolar macrophage mitochondrial bioenergetics likely contribute to innate immune dysfunction in HIV infection, and GM-CSF treatment may offer a novel therapeutic strategy for mitigating these deleterious effects.

Background Despite anti-retroviral therapy, HIV-1 infection increases the risk of pneumonia and causes oxidative stress and defective alveolar macrophage (AM) immune function. We have previously determined that HIV-1 proteins inhibit antioxidant defenses and impair AM phagocytosis by suppressing nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Given its known effects on Nrf2, we hypothesize miR-144 mediates the HIV-1 induced suppression of Nrf2. Methods Primary AMs isolated from HIV-1 transgenic (HIV-1 Tg) rats and wild type littermates (WT) as well as human monocyte-derived macrophages (MDMs) infected ex vivo with HIV-1 were used. We modulated miR-144 expression using a miR-144 mimic or an inhibitor to assay its effects on Nrf2/ARE activity and AM functions in vitro and in vivo. Results MiR-144 expression was increased in AMs from HIV-1 Tg rats and in HIV-1-infected human MDMs compared to cells from WT rats and non-infected human MDMs, respectively. Increasing miR-144 with a miR-144 mimic inhibited the expression of Nrf2 and its downstream effectors in WT rat macrophages and consequently impaired their bacterial phagocytic capacity and H2O2 scavenging ability. These effects on Nrf2 expression and AM function were reversed by antagonizing miR-144 ex vivo or in the airways of HIV-1 Tg rats in vivo, but this protection was abrogated by silencing Nrf2 expression. Conclusions Our results suggest that inhibiting miR-144 or interfering with its deleterious effects on Nrf2 attenuates HIV-1-mediated AM immune dysfunction and improves lung health in individuals with HIV.

Chronic HIV infection causes redox stress and increases the risk of acute and chronic lung injury, even when individuals are adherent to antiretroviral therapy. HIV-1 transgene expression in rats inhibits nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which regulates antioxidant defenses and alveolar epithelial cell (AEC) barrier function, but the mechanism is unknown. In this study, we present novel evidence that these pathological effects of HIV are mediated by microRNA-144 (miR-144). HIV-1 transgene expression in vivo increases the expression of miR-144 in the alveolar epithelium, and this can be replicated by direct exposure of naïve primary AECs to either Tat or gp120 ex vivo. Further, treating naïve primary AECs with a miR-144 mimic decreased the expression and activity of Nrf2 and inhibited their barrier formation. In contrast, treatment with a miR-144 antagomir increased the expression and activity of Nrf2 and improved barrier function in primary AECs isolated from HIV-1 transgenic rats. Importantly, either delivering the miR-144 antagomir intratracheally, or directly activating Nrf2 by dietary treatment with PB123, increased Nrf2 expression and barrier formation in HIV-1 transgenic rat AECs. This study provides new experimental evidence that HIV-induced inhibition of Nrf2 and consequent AEC barrier dysfunction are mediated via miR-144, and that these pathophysiological effects can be mitigated in vivo by either directly antagonizing miR-144 or activating Nrf2. Our findings suggest that targeting the inhibition of Nrf2 in individuals living with HIV could enhance their lung health and decrease the lung-specific morbidity and mortality that persists despite antiretroviral therapy.

BACKGROUND: Alcohol exposure induces TGFβ1 and renders the lung susceptible to injury and disrepair. We determined that TGFβ1 regulates myofibroblast differentiation through the loss of Thy-1 expression and consequent induction of α-SMA. TGFβ1 is important for T helper 17 (Th17) differentiation and IL-17 secretion, which in turn participates in tissue repair. We hypothesized that alcohol induces Th17 differentiation via TGFβ1 and that IL-17 produced by these cells contributes to the development of pro-fibrotic lung myofibroblasts. METHODS: Primary lung fibroblasts (PLFs) were treated with alcohol, TGFβ1, and IL-17 and then analyzed for Thy-1 expression and cell morphology. Naïve and Th17-polarized CD4(+) T cells were exposed to alcohol and assessed for IL-17 expression. CD4(+) T cells from alcohol-fed mice were analyzed for Th17 and IL-17 expression. Lungs of control-fed, bleomycin-treated and alcohol-fed, bleomycin-treated mice were analyzed for IL-17 protein expression. RESULTS: Alcohol-treated PLFs expressed lower levels of Thy-1 than untreated cells. TGFβ1 or IL-17 exposure suppressed PLF Thy-1 expression. When administered together, TGFβ1 and IL-17 additively downregulated Thy-1 expression. Exposure of naïve and Th17-polarized CD4(+) T cells to alcohol induced the Th17 phenotype and augmented their production of IL-17. CD4(+) Th17(+) levels are elevated in the peripheral compartment but not in the lungs of alcohol-fed animals. Treatment of the PLFs with IL-17 and alcohol induced α-SMA expression. Induction of α-SMA and myofibroblast morphology by IL-17 occurred selectively in a Thy-1(−) fibroblast subpopulation. Chronic alcohol ingestion augmented lung-specific IL-17 expression following bleomycin-induced lung injury. CONCLUSION: Alcohol exposure skews T cells toward a Th17 immune response that in turn primes the lung for fibroproliferative disrepair through loss of Thy-1 expression and induction of myofibroblast differentiation. These effects suggest that IL-17 and TGFβ1 contribute to fibroproliferative disrepair in the lung and targeting these proteins could limit morbidity and mortality following lung injury in alcoholic individuals.

Wide heterogeneity of disease course ranging from asymptomatic spread to respiratory failure and death has become a hallmark of the SARS-CoV-2 pandemic. While this clinical spectrum is well documented, its immunologic underpinnings are less clear. We have therefore, initiated studies of the B cell responses as they would participate in both early effector responses and in the initiation of memory formation. In terms of effector responses, we were particularly interested in the engagement and clinical correlates of the extra-follicular pathway (EF), we recently described in flaring SLE. In this systemic autoimmune disease, the EF pathway is initiated by newly activated naive B cell (aN) leading to large expansion of autoantibody-producing antibody-secreting cells through the generation of an epigenetically primed B cell precursor which are double negative (DN) for naive (IgD) and memory markers (CD27) and lacking expression of CXCR5 and CD21 (DN2). These highly activated D2 cells are also distinguished by high expression of CD11c and T-bet and are TLR7-driven. Both, TLR7-stimulation which is triggered by ssRNA and the central role played by their murine counterparts (typically characterized as Age-Associated B cells), in viral clearance, strongly supported the hypothesis that DN2 cells and the global EF pathway could be prominently engaged in COVID-19 patients. Also of note, EF B cell activation is particularly prominent in SLE patients of African-American ancestry, a population disproportionately represented in severe COVID-19. In this study we find that critically-ill patients with COVID-19 robustly upregulate constituents of the extrafollicular pathway, produce enormous numbers of antibody secreting cells, and lose unique transitional B cell populations that correlate with positive prognosis. This patient cluster associates tightly with biomarkers of poor outcomes and exhibits high rates of mortality. Thus, this B cell phenotype might serve as an immunological marker of severe COVID infection at early stages and could therefore identify a patient subset likely to benefit from targeted immunomodulatory therapy aimed at alleviating disease burden.

Background Alcohol significantly impairs antioxidant defenses and innate immune function in the lung and increases matrix metalloproteinase 9 (MMP-9) activity. The receptor for advanced glycation end products (RAGE) is a well-characterized marker of lung injury that is cleaved by MMP-9 into soluble RAGE and has not yet been examined in the alcoholic lung. We hypothesized that chronic alcohol ingestion would impair RAGE signaling via MMP-9 in the alveolar macrophage and thereby impair innate immune function. Materials and Methods Primary alveolar macrophages were isolated from control-fed or alcohol-fed rats. Real-time polymerase chain reaction (qRT-PCR), Western blotting, and enzyme-linked immunosorbent assays were performed to evaluate RAGE expression. Silencing of MMP-9 ribonucleic acid (RNA) in a rat alveolar macrophage cell line was confirmed by qRT-PCR, and immunofluorescence (IF) was used to assess the association between alcohol, MMP-9, and RAGE. Phagocytosis was assessed using flow cytometry. Sulforaphane and glutathione were used to assess the relationship between oxidative stress and RAGE. Results RAGE messenger RNA expression was significantly increased in the alveolar macrophages of alcohol-fed rats, but IF showed that membrane-bound RAGE protein expression was decreased. Lavage fluid demonstrated increased levels of soluble RAGE (sRAGE). Decreasing MMP-9 expression using si-MMP-9 abrogated the effects of alcohol on RAGE protein. Phagocytic function was suppressed by direct RAGE inhibition, and the impairment was reversed by antioxidant treatment. Conclusions Chronic alcohol ingestion reduces RAGE protein expression and increases the amount of sRAGE in alveolar lavage fluid, likely via cleavage by MMP-9. In addition, it impairs phagocytic function. Antioxidants restore membrane-bound RAGE and phagocytic function.

The advent of antiretroviral therapy has transformed infection by the type 1 human immunodeficiency virus (HIV) from a rapidly fatal disease to a chronic illness with excellent long-term survival rates. Although HIV primarily targets the adaptive arm of host immunity, it simultaneously impacts the innate immune system, and has profound implications for lung health, even when viral suppression is achieved with antiretroviral therapy. The lung has evolved a unique array of innate immune defenses, and the pathophysiological interactions between HIV and the pulmonary innate immune system deserve particular attention. In this review, we discuss work that elucidates how the components of innate immunity both respond to and are perturbed by infection with HIV.

Hypothesis-driven physical examination emphasizes the role of bedside examination in the refinement of differential diagnoses and improves diagnostic acumen. This approach has not yet been investigated as a tool to improve the ability of higher-level trainees to teach medical students.To assess the effect of teaching hypothesis-driven physical diagnosis to pulmonary fellows on their ability to improve the pulmonary examination skills of first-year medical students.Fellows and students were assessed on teaching and diagnostic skills by self-rating on a Likert scale. One group of fellows received the hypothesis-driven teaching curriculum (the "intervention" group) and another received instruction on head-to-toe examination. Both groups subsequently taught physical diagnosis to a group of first-year medical students. An oral examination was administered to all students after completion of the course.Fellows were comfortable teaching physical diagnosis to students. Students in both groups reported a lack of comfort with the pulmonary examination at the beginning of the course and improvement in their comfort by the end. Students trained by intervention group fellows outperformed students trained by control group fellows in the interpretation of physical findings (P0.05).Teaching hypothesis-driven physical examination to higher-level trainees who teach medical students improves the ability of students to interpret physical findings. This benefit should be confirmed using validated testing tools.

Alveolar macrophage (AM) immune function depends on the activation of the transcription factor PU.1 by granulocyte macrophage colony-stimulating factor. We have determined that chronic alcohol ingestion dampens PU.1 signaling via an unknown zinc-dependent mechanism; specifically, although PU.1 is not known to be a zinc-dependent transcription factor, zinc treatment reversed alcohol-mediated dampening of PU.1 signaling. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a zinc-dependent basic leucine zipper protein essential for antioxidant defenses, is also impaired by chronic alcohol ingestion and enhanced by zinc treatment. We hypothesized that the response of PU.1 to zinc treatment may result from the action of Nrf2 on PU.1. We first performed Nrf2/PU.1 protein coimmunoprecipitation on a rat AM cell line (NR8383) and found no evidence of protein-protein interactions. We then found evidence of increased Nrf2 binding to the PU.1 promoter region by chromatin immunoprecipitation. We next activated Nrf2 using either sulforaphane or an overexpression vector and inhibited Nrf2 with silencing RNA to determine whether Nrf2 could actively regulate PU.1. Nrf2 activation increased protein expression of both factors as well as gene expression of their respective downstream effectors, NAD(P)H dehydrogenase[quinone] 1 (NQO1) and cluster of differentiation antigen-14 (CD14). In contrast, Nrf2 silencing decreased the expression of both proteins, as well as gene expression of their effectors. Activating and inhibiting Nrf2 in primary rat AMs resulted in similar effects. Taken together, these findings suggest that Nrf2 regulates the expression and activity of PU.1 and that antioxidant response and immune activation are coordinately regulated within the AM.

Human immunodeficiency virus type 1 (HIV-1) is the retrovirus responsible for the development of AIDS. Its profound impact on the immune system leaves the host vulnerable to a wide range of opportunistic infections not seen in individuals with a competent immune system. Pulmonary infections dominated the presentations in the early years of the epidemic, and infectious and noninfectious lung diseases remain the leading causes of morbidity and mortality in persons living with HIV despite the development of effective antiretroviral therapy. In addition to the long known immunosuppression and infection risks, it is becoming increasingly recognized that HIV promotes the risk of noninfectious pulmonary diseases through a number of different mechanisms, including direct tissue toxicity by HIV-related viral proteins and the secondary effects of coinfections. Diseases of the airways, lung parenchyma and the pulmonary vasculature, as well as pulmonary malignancies, are either more frequent in persons living with HIV or have atypical presentations. As the pulmonary infectious complications of HIV are generally well known and have been reviewed extensively, this review will focus on the breadth of noninfectious pulmonary diseases that occur in HIV-infected individuals as these may be more difficult to recognize by general medical physicians and subspecialists caring for this large and uniquely vulnerable population.

Triggering receptor expressed on myeloid cells-1(TREM-1) is a member of the superimmunoglobulin receptor family. We have previously shown that TREM-1 prolongs survival of macrophages treated with lipoolysaccharide through Egr2-Bcl2 signaling. Recent studies suggest a role for TREM-1 in viral immunity. Human immunodeficiency virus-1 (HIV) targets the monocyte/macrophage lineage at varying stages of infection. Emerging data suggest that macrophages are key reservoirs for latent HIV even in individuals on antiretroviral therapy. Here, we investigated the potential role of TREM-1 in HIV latency in macrophages. Our data show that human macrophages infected with HIV show an increased expression of TREM-1. In parallel, direct exposure to the HIV-related proteins Tat or gp120 induces TREM-1 expression in macrophages and confers anti-apoptotic attributes.NF-κB p65 silencing identified that these proteins induce TREM-1 in p65-dependent manner. TREM-1 silencing in macrophages exposed to HIV-related proteins led to increased caspase 3 activation and reduced Bcl-2 expression, rendering them susceptible to apotosis. These novel data reveal that TREM-1 may play a critical role in establishing HIV reservoir in macrophages by inhibiting apoptosis. Therefore, targeting TREM-1 could be a novel therapeutic approach to enhance clearance of the HIV reservoir, at least within the macrophage pools.

Descriptions of sepsis can be found in humanity’s oldest written documents. It has long been recognized as a cause of severe illness and death. In the modern era, advances in the microbiology brought with them the understanding of sepsis as a severe inflammatory response to infection. Consensus conferences have provided definitions of sepsis that emphasize its many potential manifestations and allow us to study its incidence over time and space. Studies of the epidemiology of sepsis demonstrate significant variability in both design and outcome measurements, but several points remain relatively consistent. Severe sepsis and septic shock are both common problems in intensive care units (ICUs) worldwide and incidence appears to be increasing. Mortality rates are significant but appear to be improving over time. The disease is quite costly, accounting for major portions of both ICU and overall healthcare expenditure. Sepsis appears to disproportionately affect men, blacks, and patients of lower socioeconomic status in most studies and has been shown to have a genetic component as well. It is strongly associated with malignancy, HIV, obesity, and diabetes mellitus. The most common site of infection driving sepsis has been and continues to be the lungs, while the predominant etiologic agent seems to be shifting from gram-negative organisms to gram-positive organisms over time.

Although the general framework described in the joint American Thoracic Society/European Respiratory Society guidelines provides a useful and practical method for the interpretation of pulmonary function tests, several other measurements and functional indices, if understood correctly, may help in diagnosis and management of patients with respiratory diseases and in design of research protocols. This review provides information on the underlying physiology, interpretative caveats, and the evidence supporting the use of a number of these indices. Some of these measurements, such as the inspiratory fraction, inspiratory capacity/total lung capacity (IC/TLC), may offer additional prognostic information, while others, such as residual volume (RV)/TLC and forced expiratory volume in 3 s/forced vital capacity (FEV3/FVC), may help fill in the gaps between patient symptoms and more traditional indices of pulmonary function. Although most studies of non-traditional indices focus on airflow-limiting disorders, many can be fruitfully applied in other settings. Understanding the physiology that catalyzed these investigations will undoubtedly enrich the functional assessment armamentarium of the practicing clinician and researcher.

Respiratory complications occur frequently in individuals living with human immunodeficiency-1 virus (HIV) infection, and there is evidence that HIV-related oxidative stress impairs alveolar macrophage immune function. We hypothesized that nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that activates the antioxidant response element (ARE) and regulates antioxidant defenses, has an important role in alveolar macrophage (AMs) immune dysfunction in individuals with HIV infections. To test that hypothesis, we analyzed human monocyte-derived macrophages (MDMs) that were either infected with HIV-1 or were exposed to the HIV-related proteins gp120 and Tat ex vivo and determined that either stress affected the expression of Nrf2 and the Nrf2-ARE–dependent genes for NAD(P)H dehydrogenase, quinone 1 (NQO1) and glutamate-cysteine ligase, catalytic subunit (GCLC). We then determined that the expression of Nrf2, NQO1, and GCLC was significantly decreased in primary AMs isolated from HIV-1 transgenic rats. In parallel, treating a rat macrophage cell line (NR8383 cells) with the HIV-related proteins gp120 or Tat similarly decreased the gene and protein expression of Nrf2, NQO1, and GCLC. Further, phagocytic function was decreased in both human MDMs infected with HIV-1 and primary AMs from HIV-1 transgenic rats. Importantly, treating HIV-1–infected human MDMs or AMs from HIV-1 transgenic rats with sulforaphane (SFN, an Nrf2 activator) significantly improved their phagocytic function. The salutary effects of SFN were abrogated by silencing RNA to Nrf2 in wild-type rat macrophages. Our findings demonstrate that HIV-1 infection and exposure to HIV-1–related proteins inhibit Nrf2-ARE activity in the AMs and impair their phagocytic function. Treatments targeted at increasing Nrf2-ARE activity could, therefore, enhance lung innate immunity in people living with HIV-1.

Idiopathic pulmonary fibrosis (IPF) is a severe, progressive fibrotic disease of the lung of unknown etiology that affects approximately 150,000 patients in the United States. It carries a median survival of two to three years, but clinical course can vary markedly from patient to patient. There has been no established treatment for IPF, but recent advances in coordinated clinical trials through groups such as IPFnet and academia-industry partnerships have allowed this relatively rare disease to be studied in much greater depth. Historically, the default therapy for IPF was a combination of prednisone, N-acetylcysteine, and azathioprine, but recent trials have shown that this regimen actually increases mortality. An enormous body of work in recent years, spanning the bench to the bedside, has radically altered our understanding of the molecular mechanisms underlying IPF. Newer modalities, particularly those involving monoclonal antibodies targeted at specific pathways known to contribute to the fibrotic process, have generated a great deal of excitement in the field, and recent clinical trials on therapies such as pirfenidone and nintedanib herald a new era in targeted IPF therapies.

The master transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of antioxidant and phase II-metabolizing enzymes by activating the antioxidant response element (ARE) and thereby protects cells and tissues from oxidative stress. Pulmonary complications remain the leading cause of death in human immunodeficiency virus (HIV)-1-infected individuals, who display systemic oxidative stress and glutathione deficiency that can be modeled in transgenic rats where HIV-1-related viral proteins decrease glutathione levels and cause epithelial barrier dysfunction within the alveolar space by as yet unknown mechanisms. We hypothesized that HIV-1-related proteins inhibit Nrf2-mediated antioxidant defenses and thereby disrupt the normally tight alveolar epithelial barrier. Nrf2 RNA silencing dampened Nrf2/ARE activity, decreased the expression of the tight junction proteins zonula occludens-1, occludin, and claudin-18, increased paracellular permeability of alveolar epithelial monolayers derived from wild-type rats, and therefore reproduced the effects of HIV-1 transgene expression on the epithelial barrier that we had previously described. In contrast, upregulating Nrf2 activity, either by plasmid-mediated overexpression or treatment with the Nrf2 activator sulforaphane, increased the expression of ARE-dependent antioxidants, including NAD(P)H dehydrogenase, quinone 1 and glutathione, improved the expression of tight junction proteins, and restored the ability to form tight barriers in alveolar epithelial cells from HIV-1 transgenic rats. Taken together, these new findings argue that HIV-1-related proteins downregulate Nrf2 expression and/or activity within the alveolar epithelium, which in turn impairs antioxidant defenses and barrier function, thereby rendering the lung susceptible to oxidative stress and injury. Furthermore, this study suggests that activating the Nrf2/ARE pathway with the dietary supplement sulforaphane could augment antioxidant defenses and lung health in HIV-1-infected individuals.