Pathogen persistence in the respiratory tract is an important preoccupation, and of particular relevance to infectious diseases such as tuberculosis. The equilibrium between elimination of pathogens and the magnitude of the host response is a sword of Damocles for susceptible patients. The alveolar macrophage is the first sentinel of the respiratory tree and constitutes the dominant immune cell in the steady state. This immune cell is a key player in the balance between defense against pathogens and tolerance toward innocuous stimuli. This review focuses on the role of alveolar macrophages in limiting lung tissue damage from potentially innocuous stimuli and from infections, processes that are relevant to appropriate tolerance of potential causes of lung disease. Notably, the different anti-inflammatory strategies employed by alveolar macrophages and lung tissue damage control are explored. These two properties, in addition to macrophage manipulation by pathogens, are discussed to explain how alveolar macrophages may drive pathogen persistence in the airways.

Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function.

The type I interferon pathway plays a critical role in both host defense and tolerance against viral infection and thus requires refined regulatory mechanisms. RIPK3-mediated necroptosis has been shown to be involved in anti-viral immunity. However, the exact role of RIPK3 in immunity to Influenza A Virus (IAV) is poorly understood. In line with others, we, herein, show that Ripk3^-/- mice are highly susceptible to IAV infection, exhibiting elevated pulmonary viral load and heightened morbidity and mortality. Unexpectedly, this susceptibility was linked to an inability of RIKP3-deficient macrophages (Mφ) to produce type I IFN in the lungs of infected mice. In Mφ infected with IAV in vitro, we found that RIPK3 regulates type I IFN both transcriptionally, by interacting with MAVS and limiting RIPK1 interaction with MAVS, and post-transcriptionally, by activating protein kinase R (PKR)—a critical regulator of IFN-β mRNA stability. Collectively, our findings indicate a novel role for RIPK3 in regulating Mφ-mediated type I IFN anti-viral immunity, independent of its conventional role in necroptosis. Influenza A virus (IAV) is a pulmonary pathogen that presents a significant threat to human health through seasonal epidemics and occasional, highly lethal pandemics. Type I IFN is an essential component of anti-viral immunity to influenza infection and pulmonary macrophages are the major source of type I IFN. Recently, we have shown that programmed macrophage cell death (apoptosis) plays a key role in immunity to influenza infection. Interestingly, another cell death program, termed necroptosis, has been also implicated in control of viral infection via receptor-interacting serine/threonine protein kinase 3 (RIPK3). In the present study, we define a novel role of RIPK3 in regulating the type I IFN pathway to protect against lethal IAV infection, which is independent of necroptosis. RIPK3 regulates type I IFN signaling at both the transcriptional and post-transcriptional levels to sequester viral replication and protect the host against influenza infection. Thus, manipulation of the RIPK3 pathways poses a novel avenue in the development of anti-IAV treatments.

Rationale: Asthma is a frequent airway disease, and asthma control determinants have been associated with indoor allergen sensitization. The most frequent allergens are house dust mites (HDM), which act in vivo on the bronchial epithelial layer. Severe asthma has also been associated with bronchial remodeling and more specifically with increased mass of bronchial smooth muscle (BSM). However, the relationship between HDM stimulation of the bronchial epithelial layer and BSM remodeling is unknown. Objectives: To evaluate whether epithelial stimulation with HDM induces BSM cell proliferation in subjects with severe asthma. Methods: A total of 22 subjects with severe asthma and 27 subjects with no asthma were recruited. We have developed an in vitro culture model combining an epithelium layer in air–liquid interface (ALI) interacting with BSM. We assessed BSM proliferation using BrdU incorporation. We explored the role of epithelium-derived mediators using reverse-transcriptase polymerase chain reaction (RT-PCR) and ELISA in vitro and in vivo. Finally, leukotrienes receptor expression was assessed in vitro by flow cytometry and RT-PCR and ex vivo by laser microdissection and RT-PCR. Measurements and Main Results: We found that epithelial stimulation by HDM selectively increased the proliferation of asthmatic BSM cells and not that of nonasthmatic cells. The mechanism involved epithelial protease-activated receptor-2–dependent production of leukotrienes C4 associated with an overexpression of leukotrienes receptor CysLTR1 by asthmatic BSM cells in vitro and ex vivo. Conclusions: This work demonstrates the selective role of HDM on BSM remodeling in patients with severe asthma and points out different therapeutic targets at epithelial and smooth muscle levels.

Pressure-volume (PV) curves constructed over the entire lung volume range can reliably detect functional changes in mouse models of lung diseases. In the present study, we constructed full-range PV curves in healthy and elastase-treated mice using either a classic manually operated technique or an automated approach using a computer-controlled piston ventilator [flexiVent FX; Scientific Respiratory Equipment (SCIREQ), Montreal, Quebec, Canada]. On the day of the experiment, subjects were anesthetized, tracheotomized, and mechanically ventilated. Following an initial respiratory mechanics scan and degassing of the lungs with 100% O₂, full-range PV curves were constructed using either the classic or the automated technique. In control mice, superimposable curves were obtained, and statistical equivalence was attained between the two methodologies. In the elastase-treated ones, where significant changes in respiratory mechanics and lung volumes were expected, very small differences were observed between the two techniques, and the criteria for statistical equivalence were met in two out of four parameters assessed. The automated technique was adapted to rats and used to estimate the functional residual capacity (FRC) by volume subtraction. This novel approach generated FRC estimates consistent with the literature, with added accuracy relative to the existing method in diseased subjects. In conclusion, the automated technique generated full-range PV curves that were equivalent or very close to those obtained with the classic method under physiological or severe pathological conditions. The automation facilitated some technical aspects of the procedure, eased its use across species, and helped derive a more accurate estimate of FRC in preclinical models of respiratory disease.NEW & NOTEWORTHY Partial and full-range pressure-volume (PV) curves are frequently used to characterize lung disease models. Whereas automated techniques exist to construct partial PV curves, a manually operated approach is classically employed to build the full-range ones. In this study, the full-range PV curve technique was automated using a computer-controlled piston ventilator. The automation simplified the technique, facilitated its extension to other species, and inspired a novel way of estimating the functional residual capacity in laboratory rodents.