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Influenza A virus (IAV) remains a significant global public health threat, causing substantial illness and economic burden. Despite existing antiviral drugs, the emergence of resistant strains necessitates alternative therapeutic strategies. This review explores the complex interplay between the ubiquitin proteasome system (UPS) and IAV pathogenesis. We discuss how IAV manipulates the UPS to promote its lifecycle, while also highlighting how host cells utilise the UPS to counteract viral infection. Recent research on deubiquitinases as potential regulators of IAV infection is also addressed. By elucidating the multifaceted role of the UPS in IAV pathogenesis, this review aims to identify potential targets for novel therapeutic interventions., (© 2024 The Author(s). Reviews in Medical Virology published by John Wiley & Sons Ltd.)

Nasal sprays for pre-exposure prophylaxis against respiratory infections show limited protection (20-70%), largely due to their single mechanism of action-either neutralizing pathogens or blocking their entry at the nasal lining, and a failure to maximize the capture of respiratory droplets, allowing them to potentially rebound and reach deeper airways. This report introduces the Pathogen Capture and Neutralizing Spray (PCANS), which utilizes a multi-modal approach to enhance efficacy. PCANS coats the nasal cavity, capturing large respiratory droplets from the air, and serving as a physical barrier against a broad spectrum of viruses and bacteria, while rapidly neutralizing them with over 99.99% effectiveness. The formulation consists of excipients identified from the FDA's Inactive Ingredient Database and Generally Recognized as Safe list to maximize efficacy for each step in the multi-modal approach. PCANS demonstrates nasal retention for up to 8 hours in mice. In a severe Influenza A mouse model, a single pre-exposure dose of PCANS leads to a >99.99% reduction in lung viral titer and ensures 100% survival, compared to 0% in the control group. PCANS suppresses pathological manifestations and offers protection for at least 4 hours. This data suggest PCANS as a promising daily-use prophylactic against respiratory infections., (© 2024 Wiley‐VCH GmbH.)

Influenza A virus (IAV) infection while primarily affecting the lungs, is often associated with cardiovascular complications. However, the mechanisms underlying this association are not fully understood. Here, we investigated the potential role of FBXL19, a member of the Skp1-Cullin-1-F-box family of E3 ubiquitin ligase, in IAV-induced cardiac inflammation. We demonstrated that FBXL19 overexpression in endothelial cells (ECs) reduced viral titers and IAV matrix protein 1 (M1) levels while increasing antiviral gene expression, including interferon (IFN)-α, -β, and -γ and RANTES (regulated on activation normal T cell expressed and secreted) in the cardiac tissue of IAV-infected mice. Moreover, EC-specific overexpression of FBXL19 attenuated the IAV infection-reduced interferon regulatory factor 3 (IRF3) level without altering its mRNA level and suppressed cardiac inflammation. Furthermore, IAV infection triggered cellular senescence programs in the heart as indicated by the upregulation of p16 and p21 mRNA levels and the downregulation of lamin-B1 levels, which were partially reversed by FBXL19 overexpression in ECs. Our findings indicate that EC-specific overexpression of FBXL19 protects against IAV-induced cardiac damage by enhancing interferon-mediated antiviral signaling, reducing cardiac inflammation, and suppressing cellular senescence programs. NEW & NOTEWORTHY Our study reveals a novel facet of IAV infection, demonstrating that it can trigger cellular senescence within the heart. Intriguingly, upregulation of endothelial FBXL19 promotes host innate immunity, reduces cardiac senescence, and diminishes inflammation. These findings highlight the therapeutic potential of targeting FBXL19 to mitigate IAV-induced cardiovascular complications.

Respiratory tract infections represent a significant global public health concern, disproportionately affecting vulnerable populations such as children, the elderly, and immunocompromised individuals. RNA viruses, particularly influenza viruses and coronaviruses, significantly contribute to respiratory illnesses, especially in immunosuppressed and elderly individuals. Influenza A viruses (IAVs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to pose global health threats due to their capacity to cause annual epidemics, with profound implications for public health. In addition, the increase in global life expectancy is influencing the dynamics and outcomes of respiratory viral infections. Understanding the molecular mechanisms by which IAVs and SARS-CoV-2 contribute to lung disease progression is therefore crucial. The aim of this review is to comprehensively explore the impact of IAVs and SARS-CoV-2 on chronic lung diseases, with a specific focus on pulmonary fibrosis in the elderly. It also outlines potential preventive and therapeutic strategies and suggests directions for future research., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Although chronic low-grade inflammation does not cause immediate clinical symptoms, over the longer term, it can enhance other insults or age-dependent damage to organ systems and thereby contribute to age-related disorders, such as respiratory disorders, heart disease, metabolic disorders, autoimmunity, and cancer. However, the molecular mechanisms governing low-level inflammation are largely unknown. We discovered that Bcl-2-interacting killer (Bik) deficiency causes low-level inflammation even at baseline and the development of spontaneous emphysema in female but not male mice. Similarly, a single nucleotide polymorphism that reduced Bik levels was associated with increased inflammation and enhanced decline in lung function in humans. Transgenic expression of Bik in the airways of Bik-deficient mice inhibited allergen- or LPS-induced lung inflammation and reversed emphysema in female mice. Bik deficiency increased nuclear but not cytosolic p65 levels because Bik, by modifying the BH4 domain of Bcl-2, interacted with regulatory particle non-ATPase 1 (RPN1) and RPN2 and enhanced proteasomal degradation of nuclear proteins. Bik deficiency increased inflammation primarily in females because Bcl-2 and Bik levels were reduced in lung tissues and airway cells of female compared with male mice. Therefore, controlling low-grade inflammation by modifying the unappreciated role of Bik and Bcl-2 in facilitating proteasomal degradation of nuclear proteins may be crucial in treating chronic age-related diseases.

Idiopathic pulmonary fibrosis (IPF) is an irreversible and fatal lung disease that is primarily found in the elderly population, and several studies have demonstrated that aging is the major risk factor for IPF. IPF is characterized by the presence of apoptosis-resistant, senescent fibroblasts that generate an excessively stiff extracellular matrix (ECM). The ECM profoundly affects cellular functions and tissue homeostasis, and an aberrant ECM is closely associated with the development of lung fibrosis. Aging progressively alters ECM components and is associated with the accumulation of senescent cells that promote age-related tissue dysfunction through the expression of factors linked to a senescence-associated secretary phenotype (SASP). There is growing evidence that SASP factors affect various cell behaviors and influence ECM turnover in lung tissue through autocrine and/or paracrine signaling mechanisms. Since life expectancy is increasing worldwide, it is important to elucidate how aging affects ECM dynamics and turnover via SASP and thereby promotes lung fibrosis. In this review, we will focus on the molecular properties of SASP and its regulatory mechanisms. Furthermore, the pathophysiological process of ECM remodeling by SASP factors and the influence of an altered ECM from aged lungs on the development of lung fibrosis will be highlighted. Finally, recent attempts to target ECM alteration and senescent cells to modulate fibrosis will be introduced. NEW & NOTEWORTHY Aging is the most prominent nonmodifiable risk factor for various human diseases including Idiopathic pulmonary fibrosis. Aging progressively alters extracellular matrix components and is associated with the accumulation of senescent cells that promote age-related tissue dysfunction. In this review, we will discuss the pathological impact of aging and senescence on lung fibrosis via senescence-associated secretary phenotype factors and potential therapeutic approaches to limit the progression of lung fibrosis.

Caspases and poly (ADP-ribose) polymerase 1 (PARP1) have been shown to promote influenza A virus (IAV) replication. However, the relative importance and molecular mechanisms of specific caspases and their downstream substrate PARP1 in regulating viral replication in airway epithelial cells (AECs) remains incompletely elucidated. Here, we targeted caspase 2, 3, 6, and PARP1 using specific inhibitors to compare their role in promoting IAV replication. Inhibition of each of these proteins caused significant decline in viral titer, although PARP1 inhibitor led to the most robust reduction of viral replication. We previously showed that the pro-apoptotic protein Bcl-2 interacting killer (Bik) promotes IAV replication in the AECs by activating caspase 3. In this study, we found that as compared with AECs from wild-type mice, bik-deficiency alone resulted in ~ 3 logs reduction in virus titer in the absence of treatment with the pan-caspase inhibitor (Q-VD-Oph). Inhibiting overall caspase activity using Q-VD-Oph caused additional decline in viral titer by ~ 1 log in bik -/- AECs. Similarly, mice treated with Q-VD-Oph were protected from IAV-induced lung inflammation and lethality. Inhibiting caspase activity diminished nucleo-cytoplasmic transport of viral nucleoprotein (NP) and cleavage of viral hemagglutinin and NP in human AECs. These findings suggest that caspases and PARP1 play major roles to independently promote IAV replication and that additional mechanism(s) independent of caspases and PARP1 may be involved in Bik-mediated IAV replication. Further, peptides or inhibitors that target and block multiple caspases or PARP1 may be effective treatment targets for influenza infection., (© 2023. The Author(s).)

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a global health emergency. There are many similarities between SARS-CoV-2 and influenza A virus (IAV); both are single-stranded RNA viruses infecting airway epithelial cells and have similar modes of replication and transmission. Like IAVs, SARS-CoV-2 infections poses serious challenges due to the lack of effective therapeutic interventions, frequent appearances of new strains of the virus, and development of drug resistance. New approaches to control these infectious agents may stem from cellular factors or pathways that directly or indirectly interact with viral proteins to enhance or inhibit virus replication. One of the emerging concepts is that host cellular factors and pathways are required for maintaining viral genome integrity, which is essential for viral replication. Although IAVs have been studied for several years and many cellular proteins involved in their replication and pathogenesis have been identified, very little is known about how SARS-CoV-2 hijacks host cellular proteins to promote their replication. IAV induces apoptotic cell death, mediated by the B-cell lymphoma-2 (Bcl-2) family proteins in infected epithelia, and the pro-apoptotic members of this family promotes viral replication by activating host cell proteases. This review compares the life cycle and mode of replication of IAV and SARS-CoV-2 and examines the potential roles of host cellular proteins, belonging to the Bcl-2 family, in SARS-CoV-2 replication to provide future research directions., (© 2022 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.)

Extensive inflammation causes epithelial cell hyperplasia in the airways and Bcl-2-interacting killer (Bik) reduces epithelial cell and mucous cell hyperplasia without affecting resting cells to restore homeostasis. These observations suggest that Bik induces apoptosis in a cell cycle-specific manner, but the mechanisms are not understood. Mice were exposed to an allergen for 3, 14, or 30 days and Bik expression was induced in airway epithelia of transgenic mice. Bik reduced epithelial and mucous cell hyperplasia when mice were exposed to an allergen for 3 or 14 days, but not when exposure lasted for 30 days, and Ki67-positivity was reduced. In culture, Bik expression killed proliferating cells but not quiescent cells. To capture the stage of the cell cycle when Bik induces cell death, airway cells that express fluorescent ubiquitin cell cycle indicators were generated that fluoresce red or green during the G0/G1 and S/G2/M phases of the cells cycle, respectively. Regardless of the cell cycle stage, Bik expression eliminated green-fluorescent cells. Also, Bik, when tagged with a blue-fluorescent protein, was only detected in green cells. Bik phosphorylation mutants at threonine 33 or serine 35 demonstrated that phosphorylation activated Bik to induce death even in quiescent cells. Immunoprecipitation and proteomic approaches identified casein kinase IIα to be responsible for phosphorylating and activating Bik to kill cells in S/G2/M. As casein kinase 2 alpha (CKIIα) is expressed only during the G2/M phase, we conclude that Bik activation in airway epithelial cells selectively targets hyperplastic epithelial cells, while leaving resting airway cells unaffected., (© 2021 Wiley Periodicals LLC.)

Protein degradation is important for proper cellular physiology as it removes malfunctioning proteins or can provide a source for energy. Proteasomes and lysosomes, through the regulatory particles or adaptor proteins, respectively, recognize proteins destined for degradation. These systems have developed mechanisms to allow adaptation to the everchanging environment of the cell. While the complex recognition of proteins to be degraded is somewhat understood, the mechanisms that help switch the proteasomal regulatory particles or lysosomal adaptor proteins to adjust to the changing landscape of degrons, during infections or inflammation, still need extensive exploration. Therefore, this review is focused on describing the protein degradation systems and the possible sensors that may trigger the rapid adaptation of the protein degradation machinery.

Respiratory syncytial virus (RSV) is associated with enhanced progression of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. However, little is known about the role of IL-17 in RSV-induced lung injury. We first investigated the role of RSV infection in enhancing mucous cell hyperplasia (MCH) and airspace enlargement in the lungs of mice injured with elastase and LPS (E/LPS). Mice injured with E/LPS had an enhanced and prolonged neutrophilic response to RSV that was associated with decreased levels of type I IFN and increased levels of IL-17, IL-23, CXCL-1, granulocyte colony stimulating factor (GCSF), CXCL-5, and matrix metalloproteinase (MMP)-9. In addition, extent of MCH and mean weighted alveolar space were increased significantly in the lungs of E/LPS-injured mice infected with RSV compared with E/LPS-only or RSV-only controls. Interestingly, immunodepletion of IL-17 before viral infection diminished the RSV-driven MCH and airspace enlargement in the E/LPS-injured animals, suggesting that IL-17 may be a therapeutic target for MCH and airspace enlargement when enhanced by RSV infection.

Hyperplastic airway epithelial cells may be the cause for increased risk for lung cancer in patients with chronic lung diseases. The B-cell lymphoma 2 (Bcl-2) family member, Bcl-2-interacting killer (BIK), triggers cell death specifically in these hyperplastic cells because of adequate presence of Death-associated Protein Kinase 1 (DAPk1), BCL-2 Antagonist Killer (BAK), and Extracellular Signal-regulated Kinase 1/ 2 (ERK1/2). Therefore, BIK may be a useful tool to control the development of lung cancer in patients with chronic diseases.

IFN-γ is known as a pro-inflammatory cytokine, but can also block inflammation in certain chronic diseases although the underlying mechanisms are poorly understood. We found that IFN-γ rapidly induced Noxa expression and that extent of inflammation by repeated house dust mite exposure was enhanced in noxa -/- compared with noxa +/+ mice. Noxa expression blocked transforming necrosis factor alpha (TNF-α)-induced nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of pro-inflammatory cytokines. Noxa did not affect TNF-α-induced IκBα phosphorylation but the degradation of 48-chain-ubiquitylated IκBα. The Cys25 of Noxa was cross-linked with Cys137 of phospho-HSP27 and both proteins were required for blocking the degradation of ubiquitylated IκBα. Because phospho-HSP27 is present in airway epithelial cells and not in fibroblasts or thymocytes, we generated transgenic mice that inducibly expressed Noxa in airway epithelia. These mice showed protection from allergen-induced inflammation and mucous cell metaplasia by blocking nuclear translocation of NF-κB. Further, we identified a Noxa-derived peptide that prolonged degradation of 48-chain-ubiquitylated IκBα, blocked nuclear translocation of NF-κB, and reduced allergen-induced inflammation in mice. These results suggest that the anti-inflammatory role of the Noxa protein may be restricted to airway epithelial cells and the use of Noxa for therapy of chronic lung diseases may be associated with reduced side effects.

Bik reduces hyperplastic epithelial cells by releasing calcium from endoplasmic reticulum stores and causing apoptosis, but the detailed mechanisms are not known. Here we report that Bik dissociates the Bak/Bcl-2 complex to enrich for ER-associated Bak and interacts with the kinase domain of DAPk1 to form Bik-DAPk1-ERK1/2-Bak complex. Bik also disrupts the Bcl2-IP 3 R interaction to cause ER Ca 2+ release. The ER-associated Bak interacts with the kinase and calmodulin domains of DAPk1 to increase the contact sites of ER and mitochondria, and facilitate ER Ca 2+ uptake by mitochondria. Although the Bik BH3 helix was sufficient to enrich for ER-Bak and elicit ER Ca 2+ release, Bik-induced mitochondrial Ca 2+ uptake is blocked with reduced Bak levels. Further, the Bik-derived peptide reduces allergen- and cigarette smoke-induced mucous cell hyperplasia in mice and in differentiated primary human airway epithelial cultures. Therefore, Bik peptides may have therapeutic potential in airway diseases associated with chronic mucous hypersecretion.Bcl-2 interacting killer (Bik) decreases airway epithelial hyperplasia via apoptosis mediated by calcium release from the endoplasmic reticulum (ER), but the mechanism is unclear. Here the authors show that Bik promotes Bak enrichment at the ER to tether mitochondria for efficient calcium transfer.

Objective: House dust mite (HDM) exposure is used to model experimental asthma in mice. However, a direct comparison of inflammatory responses following continuous versus intermittent HDM exposure has not been reported. Therefore, we investigated whether the HDM dose at sensitization or challenge affects extent of inflammation in mice that were either continuously or intermittently sensitized with HDM., Materials and Methods: C57BL/6 mice received either 10 continuous exposures with 10 μg HDM per exposure or two intermittent HDM exposures over a period of two weeks and were subsequently challenged by three instillations with HDM during the third week. For the intermittent model, mice were sensitized with 1 or 10 μg HDM and challenged on three consecutive days with 1 or 10 μg HDM. Inflammatory cells in the bronchoalveolar lavage fluid and epithelial cell hyperplasia and mucous cell metaplasia were quantified., Results: Significantly higher levels of inflammation and mucous cell metaplasia were observed when mice were sensitized intermittently compared with continuously. Intermittent sensitization and challenge with 10 μg HDM caused maximum inflammation, mucous cell metaplasia, and epithelial cell hyperplasia. However, sensitization with 1 μg HDM only also showed increased inflammation when challenged with 10 μg HDM., Discussion: These findings suggest major differences in adaptive immunity, depending on the sensitization protocol., Conclusions: Because of significant differences, the HDM sensitization protocol should be carefully considered when designing studies to investigate the underlying mechanisms of immunity in mouse models of asthma.

Background: Airway epithelial cells (AECs) are crucial for mucosal and adaptive immunity but whether these cells respond in a memory-dependent manner is poorly studied. Previously, we have reported that LPS intratracheal instillation in rodents causes extensive neutrophilic inflammation and airway epithelial cell hyperplasia accompanied by mucous cell metaplasia (MCM). And the resolution process required a period of 40 d for the inflammation to subside and the lung epithelia to resemble the non-exposed condition. Therefore, the present study investigated the memory-dependent response of airway epithelial cells to a secondary LPS challenge after the initial inflammation was resolved., Methods: Airway epithelial and mucous cells were assessed in response to a secondary LPS challenge in F344/N rats, and in C57BL/6 wild-type (Foxn1 WT ) and T cell-deficient athymic (Foxn1 nu ) mice that were instilled with LPS or saline 40 d earlier. Epithelial expression of TLR4, EGFR, and phosphorylated-ERK1/2 (pERK) were also analyzed., Results: LPS-pretreated F344/N rats responded with elevated numbers of AECs after saline challenge and with 3-4-fold increased MCM following the LPS challenge in LPS- compared with saline-pretreated rats. LPS-pretreated rats showed 5-fold higher number of AECs expressing TLR4 apically than saline-pretreated rats. Also, the expression of EGFR was increased in LPS-pretreated rats along with the number of AECs with active or nuclear pERK, and the levels were further increased upon LPS challenge. LPS-pretreated Foxn1 nu compared with Foxn1 WT mice showed increased MCM and elevated levels of TLR4, EGFR, and nuclear pERK at 40 d after LPS instillation. LPS challenge further augmented MCM rapidly in Foxn1 nu compared with Foxn1 WT mice., Conclusion: Together, these data suggest that AECs preserve an 'innate memory' that drives a rapid mucous phenotype via spatiotemporal regulation of TLR4 and EGFR. Further, T cells may suppress the sustained elevated expression of TLR4 and EGFR and thereby the hyperactive epithelial response.

Background: The length of time for cigarette smoke (CS) exposure to cause emphysema in mice is drastically reduced when CS exposure is combined with viral infection. However, the extent of inflammatory responses and lung pathologies of mice exposed to CS and infected with influenza A virus (IAV), respiratory syncytial virus (RSV), or treated with the viral derivative dsRNA (polyinosine-polycytidylic acid [poly (I:C)] have not been compared., Methods: Mice were exposed to CS or filtered air for 4 weeks and received a single dose of vehicle, AV, or RSV infection and extent of inflammation and emphysema was evaluated 14 d later. In another set of experiments, mice were instilled with poly (I:C) twice a week during the third and fourth weeks of CS exposure and immediately analyzed for extent of inflammation and lung pathologies., Results: In CS-exposed mice, inflammation was characterized mainly by macrophages, lymphocytes, and neutrophils after IAV infection, mainly by lymphocytes, and neutrophils after RSV infection, and mainly by lymphocytes and neutrophils after poly (I:C) instillations. Despite increased inflammation, extent of emphysema by poly (I:C) was very mild; but was robust and similar for both IAV and RSV infections with enhanced MMP-12 mRNA expression and TUNEL positivity. Both IAV and RSV infections increased the levels of IL-17, IL-1β, IL-12b, IL-18, IL-23a, Ccl-2, Ccl-7 mRNAs in the lungs of CS-exposed mice with IAV causing more increases than RSV., Conclusion: CS-induced inflammatory responses and extent of emphysematous changes differ depending on the type of viral infection. These animal models may be useful to study the mechanisms by which different viruses exacerbate CS-induced inflammation and emphysema.

Influenza virus induces apoptosis in infected cells to promote viral replication by manipulating the host cell death signaling pathway. Although some Bcl-2 family proteins play a role in the replication of influenza A virus (IAV), the role of cell death pathways in the viral replication cycle is unclear. We investigated whether deficiency of the proapoptotic Bcl-2 family protein, Bik, plays a role in IAV replication. IAV replication was attenuated in mouse airway epithelial cells (MAECs) from bik(-/-) compared with bik(+/+) mice, as indicated by reduced viral titers. Bik(-/-) MAECs showed more stable transepithelial resistance after infection than did bik(+/+) MAECs, were less sensitive to infection-induced cell death, and released fewer copies of viral RNA. Similar results were obtained when Bik expression was suppressed in human airway epithelial cells (HAECs). Bik(+/+) mice lost weight drastically and died within 8 days of infection, whereas 75% of bik(-/-) mice survived infection for 14 days and were 10-fold less likely to die from infection compared with bik(+/+) mice. IAV infection activated caspase 3 in bik(+/+) but not in bik(-/-) MAECs. Cleavage of viral nucleoprotein and M2 proteins were inhibited in bik(-/-) MAECs and when caspase activation was inhibited in HAECs. Furthermore, Bik deficiency impaired cytoplasmic export of viral ribonucleoprotein. These studies suggest a link between Bik-mediated caspase activation and cleavage of viral proteins. Thus, inhibition of proapoptotic host factors such as Bik and downstream mediators of cell death may represent a novel approach to influenza treatment.

Rationale: Aberrant regulation of airway epithelial cell numbers in airways leads to increased mucous secretions in chronic lung diseases such as chronic bronchitis. Because the Bcl-2 family of proteins is crucial for airway epithelial homeostasis, identifying the players that reduce cigarette smoke (CS)-induced mucous cell metaplasia can help to develop effective therapies., Objectives: To identify the Bcl-2 family of proteins that play a role in reducing CS-induced mucous cell metaplasia., Methods: We screened for dysregulated expression of the Bcl-2 family members., Measurements and Main Results: We identified Bik to be significantly reduced in bronchial brushings of patients with chronic epithelial cell hyperplasia compared with nondiseased control subjects. Reduced Bik but increased MUC5AC mRNA levels were also detected when normal human airway epithelial cells (HAECs) were exposed to CS or when autopsy tissues from former smokers with and without chronic bronchitis were compared. Similarly, exposure of C57Bl/6 mice to CS resulted in increased numbers of epithelial and mucous cells per millimeter of basal lamina, along with reduced Bik but increased Muc5ac expression, and this change was sustained even when mice were allowed to recover in filtered air for 8 weeks. Restoring Bik expression significantly suppressed CS-induced mucous cell metaplasia in differentiated primary HAEC cultures and in airways of mice in vivo. Bik blocked nuclear translocation of phospho-ERK1/2 to induce apoptosis of HAECs. The conserved Leu61 within Bik and ERK1/2 activation were essential to induce cell death in hyperplastic mucous cells., Conclusions: These studies show that CS suppresses Bik expression to block airway epithelia cell death and thereby increases epithelial cell hyperplasia in chronic bronchitis.

IFNgamma induces cell death in epithelial cells, but the mediator for this death pathway has not been identified. In this study, we find that expression of Bik/Blk/Nbk is increased in human airway epithelial cells (AECs [HAECs]) in response to IFNgamma. Expression of Bik but not mutant BikL61G induces and loss of Bik suppresses IFNgamma-induced cell death in HAECs. IFNgamma treatment and Bik expression increase cathepsin B and D messenger RNA levels and reduce levels of phospho-extracellular regulated kinase 1/2 (ERK1/2) in the nuclei of bik(+/+) compared with bik(-/-) murine AECs. Bik but not BikL61G interacts with and suppresses nuclear translocation of phospho-ERK1/2, and suppression of ERK1/2 activation inhibits IFNgamma- and Bik-induced cell death. Furthermore, after prolonged exposure to allergen, hyperplastic epithelial cells persist longer, and nuclear phospho-ERK is more prevalent in airways of IFNgamma(-/-) or bik(-/-) compared with wild-type mice. These results demonstrate that IFNgamma requires Bik to suppress nuclear localization of phospho-ERK1/2 to channel cell death in AECs.