BACKGROUND: One of the most common entry gates for systemic infection is the lung. In humans, pulmonary infections can lead to significant neurological impairment, ranging from acute sickness behavior to long-term disorders. Surfactant proteins (SP), essential parts of the pulmonary innate immune defense, have been detected in the brain of rats and humans. Recent evidence suggests that SP-A, the major protein component of surfactant, also plays a functional role in modulating neuroinflammation. This study aimed to determine whether SP-A deficiency affects the inflammatory response in the brain of adult mice during pulmonary infection.
METHODS: Adult male wild-type (WT, n = 72) and SP-A-deficient (SP-A-/-, n = 72) mice were oropharyngeally challenged with lipopolysaccharide (LPS), Pseudomonas aeruginosa (P. aeruginosa), or PBS (control). Both, behavioral assessment and subsequent brain tissue analysis, were performed 24, 48, and 72 h after challenge. The brain concentrations of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β were determined by ELISA. Quantitative rtPCR was used to detect SP-A mRNA expression in brain homogenates and immunohistochemistry was applied for the detection of SP-A protein expression in brain coronal slices.
RESULTS: SP-A mRNA and histological evidence of protein expression were detected in both the lungs and brains of WT mice, with significantly higher amounts in lung samples. SP-A-/- mice exhibited significantly higher baseline concentrations of brain TNF-α, IL-6, and IL-1β compared to WT mice. Oropharyngeal application of either LPS or P. aeruginosa elicited significantly higher brain levels of TNF-α and IL-1β in SP-A-/- mice compared to WT mice at all time points. In comparison, behavioral impairment as a measure of sickness behavior, was significantly stronger in WT than in SP-A-/- mice, particularly after LPS application.
CONCLUSIONS: SP-A is known for its anti-inflammatory role in the pulmonary immune response to bacterial infection. Recent evidence suggests that in an abdominal sepsis model SP-A deficiency can lead to increased cytokine levels in the brain. Our results extend this perception and provide evidence for an anti-inflammatory role of SP-A in the brain of adult WT mice after pulmonary infection.

Given the various clinical manifestations that characterize Coronavirus Disease 2019 (COVID-19), the scientific community is constantly searching for biomarkers with prognostic value. Surfactant proteins A (SP-A) and D (SP-D) are collectins that play a crucial role in ensuring proper alveolar function and an alteration of their serum levels was reported in several pulmonary diseases characterized by Acute Respiratory Distress Syndrome (ARDS) and pulmonary fibrosis. Considering that such clinical manifestations can also occur during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we wondered if these collectins could act as prognostic markers. In this regard, serum levels of SP-A and SP-D were measured by enzyme immunoassay in patients with SARS-CoV-2 infection (n = 51) at admission (T0) and after seven days (T1) and compared with healthy donors (n = 11). SP-D increased in COVID-19 patients compared to healthy controls during the early phases of infection, while a significant reduction was observed at T1. Stratifying SARS-CoV-2 patients according to disease severity, increased serum SP-D levels were observed in severe compared to mild patients. In light of these results, SP-D, but not SP-A, seems to be an eligible marker of COVID-19 pneumonia, and the early detection of SP-D serum levels could be crucial for preventive clinical management.

BACKGROUND: Severe cases of COVID-19 often lead to the development of acute respiratory syndrome, a critical condition believed to be caused by the harmful effects of SARS-CoV-2 on type II alveolar cells. These cells play a crucial role in producing pulmonary surfactants, which are essential for proper lung function. Specifically focusing on surfactant proteins, including Surfactant protein A (SP-A), Surfactant protein B, Surfactant protein C, and Surfactant protein D (SP-D), changes in the levels of pulmonary surfactants may be a significant factor in the pathological changes seen in COVID-19 infection.
OBJECTIVE: This study aims to gain insights into surfactants, particularly their impacts and changes during COVID-19 infection, through a comprehensive review of current literature. The study focuses on the function of surfactants as prognostic markers, diagnostic factors, and essential components in the management and treatment of COVID-19.
RESULTS: In general, pulmonary surfactants serve to reduce the surface tension at the gas-liquid interface, thereby significantly contributing to the regulation of respiratory mechanics. Additionally, these surfactants play a crucial role in the innate immune system within the pulmonary microenvironment. Within the spectrum of COVID-19 infections, a compelling association is observed, characterized by elevated levels of SP-D and SP-A across a range of manifestations from mild to severe pneumonia. The sudden decline in respiratory function observed in COVID-19 patients may be attributed to the decreased synthesis of surfactants by type II alveolar cells.
CONCLUSIONS: Collectin proteins such as SP-A and SP-D show promise as biomarkers, offering potential avenues for predicting and monitoring pulmonary alveolar injury in the context of COVID-19. This clarification enhances our understanding of the molecular complexities contributing to respiratory complications in severe COVID-19 cases, providing a foundation for targeted therapeutic approaches using surfactants and refined clinical management strategies.

BACKGROUND: The alveolar epithelium is exposed to numerous stimuli, such as chemicals, viruses, and bacteria that cause a variety of pulmonary diseases through inhalation. Alveolar epithelial cells (AECs) cultured in vitro are a valuable tool for studying the impacts of these stimuli and developing therapies for associated diseases. However, maintaining the proliferative capacity of AECs in vitro is challenging. In this study, we used a cocktail of three small molecule inhibitors to cultivate AECs: Y-27632, A-83-01, and CHIR99021 (YAC). These inhibitors reportedly maintain the proliferative capacity of several types of stem/progenitor cells.
RESULTS: Primary human AECs cultured in medium containing YAC proliferated for more than 50 days (over nine passages) under submerged conditions. YAC-treated AECs were subsequently cultured at the air-liquid interface (ALI) to promote differentiation. YAC-treated AECs on ALI day 7 formed a monolayer of epithelial tissue with strong expression of the surfactant protein-encoding genes SFTPA1, SFTPB, SFTPC, and SFTPD, which are markers for type II AECs (AECIIs). Immunohistochemical analysis revealed that paraffin sections of YAC-treated AECs on ALI day 7 were mainly composed of cells expressing surfactant protein B and prosurfactant protein C.
CONCLUSIONS: Our results indicate that YAC-containing medium could be useful for expansion of AECIIs, which are recognized as local stem/progenitor cells, in the alveoli.

Heat exposure induces excessive hyperthermia associated with systemic inflammatory response that leads to multiple organ dysfunction including acute lung injury. However, how heat impairs the lung remains elusive so far. We aimed to explore the underlying mechanism by focusing on leucine-rich repeat kinase 2 (LRRK2), which was associated with lung homeostasis. Both in vivo and in vitro models were induced by heat exposure. Firstly, heat exposure exerted core temperature (Tc) disturbance, pulmonary dysfunction, atelectasis, inflammation, impaired energy metabolism, and reduced surfactant proteins in the lung of mice. In addition, decreased LRRK2 expression and increased heat shock proteins (HSPs) 70 were observed with heat exposure in both the lung of mice and alveolar type II epithelial cells (AT2). Furthermore, LRRK2 inhibition aggravated heat exposure-initiated Tc dysregulation, injury in the lung and AT2 cells, and enhanced HSP70 expression. In conclusion, LRRK2 is involved in heat-induced acute lung injury and AT2 cell dysfunction.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of interstitial lung diseases (ILDs), marked by an ongoing, chronic fibrotic process within the lung tissue. IPF leads to an irreversible deterioration of lung function, ultimately resulting in an increased mortality rate. Therefore, the focus has shifted towards the biomarkers that might contribute to the early diagnosis, risk assessment, prognosis, and tracking of the treatment progress, including those associated with epithelial injury.
METHODS: We conducted this review through a systematic search of the relevant literature using established databases such as PubMed, Scopus, and Web of Science. Selected articles were assessed, with data extracted and synthesized to provide an overview of the current understanding of the existing biomarkers for IPF.
RESULTS: Signs of epithelial cell damage hold promise as relevant biomarkers for IPF, consequently offering valuable support in its clinical care. Their global and standardized utilization remains limited due to a lack of comprehensive information of their implications in IPF.
CONCLUSIONS: Recognizing the aggressive nature of IPF among interstitial lung diseases and its profound impact on lung function and mortality, the exploration of biomarkers becomes pivotal for early diagnosis, risk assessment, prognostic evaluation, and therapy monitoring.

Organoids can meet the needs between the use of cell culture and in vivo work, bringing together aspects of multicellular tissues, providing a more similar in vitro system for the study of various components, including host-interactions with pathogens and drug response. Organoids are structures that resemble organs in vivo, originating from pluripotent stem cells (PSCs) or adult stem cells (ASCs). There is great interest in deepening the understanding of the use of this technology to produce information about fungal infections and their treatments. This work aims the use 2D human lung organoid derived from human embryonic stem cells (hESCs), to investigate Cryptococcus neoformans-host interactions. C. neoformans is an opportunistic fungus acquired by inhalation that causes systemic mycosis mainly in immunocompromised individuals. Our work highlights the suitability of human minilungs for the study of C. neoformans infection (adhesion, invasion and replication), the interaction with the surfactant and induction of the host\'s alveolar pro-inflammatory response.

Bronchopulmonary dysplasia (BPD) is a multi-factorial disease that results from multiple clinical factors, including lung immaturity, mechanical ventilation, oxidative stress, pulmonary congestion due to increasing cardiac blood shunting, nutritional and immunological factors. Twin studies have indicated that susceptibility to BPD can be strongly inherited in some settings. Studies have reported associations between common genetic variants and BPD in preterm infants. Recent genomic studies have highlighted a potential role for molecular pathways involved in inflammation and lung development in affected infants. Rare mutations in genes encoding the lipid transporter ATP-binding cassette, sub-family A, member 3 (ABCA3 gene) which is involved in surfactant synthesis in alveolar type II cells, as well as surfactant protein B (SFTPB) and C (SFTPC) can also result in severe form of neonatal-onset interstitial lung diseases and may also potentially affect the course of BPD. This chapter summarizes the current state of knowledge on the genetics of BPD.

The alveolar epithelium is covered by a non-cellular layer consisting of an aqueous hypophase topped by pulmonary surfactant, a lipo-protein mixture with surface-active properties. Exposure to cigarette smoke (CS) affects lung physiology and is linked to the development of several diseases. The macroscopic effects of CS are determined by several types of cell and molecular dysfunction, which, among other consequences, lead to surfactant alterations. The purpose of this review is to summarize the published studies aimed at uncovering the effects of CS on both the lipid and protein constituents of surfactant, discussing the molecular mechanisms involved in surfactant homeostasis that are altered by CS. Although surfactant homeostasis has been the topic of several studies and some molecular pathways can be deduced from an analysis of the literature, it remains evident that many aspects of the mechanisms of action of CS on surfactant homeostasis deserve further investigation.

Pompe disease is an autosomal recessive glycogen storage disease caused by mutations in the gene that encodes acid alpha-glucosidase (GAA)-an enzyme responsible for hydrolyzing lysosomal glycogen. GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption. Glycogen accumulation in skeletal muscles, motor neurons, and airway smooth muscle cells is known to contribute to respiratory insufficiency in Pompe disease. However, the impact of GAA deficiency on the distal alveolar type 1 and type 2 cells (AT1 and AT2) has not been evaluated. AT1 cells rely on lysosomes for cellular homeostasis so that they can maintain a thin barrier for gas exchange, whereas AT2 cells depend on lysosome-like structures (lamellar bodies) for surfactant production. Using a mouse model of Pompe disease, the Gaa-/- mouse, we investigated the consequences of GAA deficiency on AT1 and AT2 cells using histology, pulmonary function and mechanics, and transcriptional analysis. Histological analysis revealed increased accumulation of lysosomal-associated membrane protein 1 (LAMP1) in the Gaa-/- mice lungs. Furthermore, ultrastructural examination showed extensive intracytoplasmic vacuoles enlargement and lamellar body engorgement. Respiratory dysfunction was confirmed using whole body plethysmography and forced oscillometry. Finally, transcriptomic analysis demonstrated dysregulation of surfactant proteins in AT2 cells, specifically reduced levels of surfactant protein D in the Gaa-/- mice. We conclude that GAA enzyme deficiency leads to glycogen accumulation in the distal airway cells that disrupts surfactant homeostasis and contributes to respiratory impairments in Pompe disease.NEW & NOTEWORTHY This research highlights the impact of Pompe disease on distal airway cells. Prior to this work, respiratory insufficiency in Pompe disease was classically attributed to pathology in respiratory muscles and motor neurons. Using the Pompe mouse model, we note significant pathology in alveolar type 1 and 2 cells with reductions in surfactant protein D and disrupted surfactant homeostasis. These novel findings highlight the potential contributions of alveolar pathology to respiratory insufficiency in Pompe disease.