Paradoxical effects of cigarette smoke and COPD on SARS-CoV-2 infection and disease.

BACKGROUND: How cigarette smoke (CS) and chronic obstructive pulmonary disease (COPD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection and severity is controversial. We investigated the effects of COPD and CS on the expression of SARS-CoV-2 entry receptor ACE2 in vivo in COPD patients and controls and in CS-exposed mice, and the effects of CS on SARS-CoV-2 infection in human bronchial epithelial cells in vitro. METHODS: We quantified: (1) pulmonary ACE2 protein levels by immunostaining and ELISA, and both ACE2 and/or TMPRSS2 mRNA levels by RT-qPCR in two independent human cohorts; and (2) pulmonary ACE2 protein levels by immunostaining and ELISA in C57BL/6 WT mice exposed to air or CS for up to 6 months. The effects of CS exposure on SARS-CoV-2 infection were evaluated after in vitro infection of Calu-3 cells and differentiated human bronchial epithelial cells (HBECs), respectively. RESULTS: ACE2 protein and mRNA levels were decreased in peripheral airways from COPD patients versus controls but similar in central airways. Mice exposed to CS had decreased ACE2 protein levels in their bronchial and alveolar epithelia versus air-exposed mice. CS treatment decreased viral replication in Calu-3 cells, as determined by immunofluorescence staining for replicative double-stranded RNA (dsRNA) and western blot for viral N protein. Acute CS exposure decreased in vitro SARS-CoV-2 replication in HBECs, as determined by plaque assay and RT-qPCR. CONCLUSIONS: ACE2 levels were decreased in both bronchial and alveolar epithelial cells from COPD patients versus controls, and from CS-exposed versus air-exposed mice. CS-pre-exposure potently inhibited SARS-CoV-2 replication in vitro. These findings urge to investigate further the controversial effects of CS and COPD on SARS-CoV-2 infection.

Paradoxical effects of cigarette smoke and COPD on SARS-CoV2 infection and disease.

INTRODUCTION: How cigarette smoke (CS) and chronic obstructive pulmonary disease (COPD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severity is controversial. We investigated the protein and mRNA expression of SARS-CoV-2 entry receptor ACE2 and proteinase TMPRSS2 in lungs from COPD patients and controls, and lung tissue from mice exposed acutely and chronically to CS. Also, we investigated the effects of CS exposure on SARS-CoV-2 infection in human bronchial epithelial cells. METHODS: In Cohort 1, ACE2-positive cells were quantified by immunostaining in FFPE sections from both central and peripheral airways. In Cohort 2, we quantified pulmonary ACE2 protein levels by immunostaining and ELISA, and both ACE2 and TMPRSS2 mRNA levels by RT-qPCR. In C57BL/6 WT mice exposed to air or CS for up to 6 months, pulmonary ACE2 protein levels were quantified by triple immunofluorescence staining and ELISA. The effects of CS exposure on SARS-CoV-2 infection were evaluated after 72hr in vitro infection of Calu-3 cells. After SARS-CoV-2 infection, the cells were fixed for IF staining with dsRNA-specific J2 monoclonal Ab, and cell lysates were harvested for WB of viral nucleocapsid (N) protein. Supernatants (SN) and cytoplasmic lysates were obtained to measure ACE2 levels by ELISA. RESULTS: In both human cohorts, ACE2 protein and mRNA levels were decreased in peripheral airways from COPD patients versus both smoker and NS controls, but similar in central airways. TMPRSS2 levels were similar across groups. Mice exposed to CS had decreased ACE2 protein levels in their bronchial and alveolar epithelia versus air-exposed mice exposed to 3 and 6 months of CS. In Calu3 cells in vitro, CS-treatment abrogated infection to levels below the limit of detection. Similar results were seen with WB for viral N protein, showing peak viral protein synthesis at 72hr. CONCLUSIONS: ACE2 levels were decreased in both bronchial and alveolar epithelial cells from uninfected COPD patients versus controls, and from CS-exposed versus air-exposed mice. CS-pre-treatment did not affect ACE2 levels but potently inhibited SARS-CoV-2 replication in this in vitro model. These findings urge to further investigate the controversial effects of CS and COPD on SARS-CoV2 infection.

Opioid-mediated Sertoli cells apoptosis is involved in testicular homeostasis and/or reproductive dysfunction.

OBJECTIVES:  The opioid system may exert positive direct and/or indirect effects on spermatogenesis at multiple levels including the levels of the central nervous system and at the testes/sperm levels. However, long term opioid use could be associated with several reproductive complications that place the users at risk of hypogonadism and even infertility. There is little available information regarding the contribution of opioids and their apoptotic effects on testis Sertoli cells. Here, the effects of DAMGO (mu opioid receptor's agonist), DPDPE (delta opioid receptor's agonist) and DYN 1-9 (kappa opioid receptor's agonist) on Sertoli cell viability and apoptosis were investigated. METHODS: Cultured Sertoli cells were exposed to each agonist (0.1-100 µM, for 24 or 48 hours) and their apoptotic effects were investigated. RESULTS: Cell viability was decreased and apoptosis was increased in the cells exposed to DAMGO in a concentration-dependent manner, while in the cells exposed to DPDPE, no significant changes were observed. In cells exposed to DYN 1-9, the viability did not significantly change, however apoptosis increased significantly, following the exposure to the high concentration of DYN 1-9. CONCLUSION: These data suggest that mu and Kappa, but not delta receptors mediated apoptosis in Sertoli cells may be involved, at least in part, in testicular homeostasis and/or reproductive dysfunction (Tab. 1, Fig. 3, Ref. 52).

Protective role of γδ T cells in cigarette smoke and influenza infection.

Airborne pathogens commonly trigger severe respiratory failure or death in smokers with lung disease. Cigarette smoking compromises the effectiveness of innate immunity against infections but the underlying mechanisms responsible for defective acquired immune responses in smokers remains less clear. We found that mice exposed to chronic cigarette smoke recovered poorly from primary Influenza A pneumonia with reduced type I and II interferons (IFNs) and viral-specific immunoglobulins, but recruited γδ T cells to the lungs that predominantly expressed interleukin 17A (IL-17A). Il-17a-/- mice exposed to smoke and infected with Influenza A also recruited γδ T cells to the lungs, but in contrast to wild-type mice, expressed increased IFNs, made protective influenza-specific antibodies, and recovered from infection. Depletion of IL-17A with blocking antibodies significantly increased T-bet expression in γδ T cells and improved recovery from acute Influenza A infection in air, but not smoke-exposed mice. In contrast, when exposed to smoke, γδ T cell deficient mice failed to mount an effective immune response to Influenza A and showed increased mortality. Our findings demonstrate a protective role for γδ T cells in smokers and suggest that smoke-induced increase in IL-17A inhibits the transcriptional programs required for their optimal anti-viral responses. Cigarette smoke induces IL-17A expression in the lungs and inhibits γδ T-cell-mediated protective anti-viral immune responses.

The effect of celecoxib and its combination with imatinib on human HT-29 colorectal cancer cells: Involvement of COX-2, Caspase-3, VEGF and NF-κB genes expression.

It has been shown that combination of imatinib (IM) with other agents may have some advantages in avoiding toxicity and resistance caused by this drug. The selective cyclooxygenase-2 inhibitor, celecoxib (CX), has been known to have antitumor and chemo-sensitizing effect in the treatment of colorectal cancer. In this study, we investigated the effectiveness of CX and its combination with anticancer agent IM on human colorectal cancer HT-29 cell and their probable molecular targets. Cultured HT-29 cells were exposed to IC50 dose of CX, IM, and their combination (half dose of IC50) for 24 hours to assess their effect on proliferation inhibition by MTT assay. The caspase-3 activity was estimated in HT-29 cells with colorimetric kit. COX-2, Caspase-3, VEGF and NF-κB genes expression was also investigated using real-time PCR method. Combined treatment with IM and CX, resulted in a significant (P˂0.05) decrease in cell viability and increased caspase-3 enzyme activity. Decreased COX-2 gene expression has been found in CX and combined treated group. Significant increase in Caspase-3 gene expression has been shown in IM and combined treated cells. In conclusion, the present in vitro study with colon cancer cell line demonstrated that CX and its combination with IM improved the anticancer activity of each component. Caspase-3 and COX-2 dependent molecular targets seem to be involved in mediating the anti-proliferative effects of IM and CX combination. Of course, the other molecular pathways are also likely to play the role and should be explored in future studies.

Activation of C3a receptor is required in cigarette smoke-mediated emphysema.

Exposure to cigarette smoke can initiate sterile inflammatory responses in the lung and activate myeloid dendritic cells (mDCs) that induce differentiation of T helper type 1 (Th1) and Th17 cells in the emphysematous lungs. Consumption of complement proteins increases in acute inflammation, but the contribution of complement protein 3 (C3) to chronic cigarette smoke-induced immune responses in the lung is not clear. Here, we show that following chronic exposure to cigarette smoke, C3-deficient (C3(-/-)) mice develop less emphysema and have fewer CD11b(+)CD11c(+) mDCs infiltrating the lungs as compared with wild-type mice. Proteolytic cleavage of C3 by neutrophil elastase releases C3a, which in turn increases the expression of its receptor (C3aR) on lung mDCs. Mice deficient in the C3aR (C3ar(-/-)) partially phenocopy the attenuated responses to chronic smoke observed in C3(-/-) mice. Consistent with a role for C3 in emphysema, C3 and its active fragments are deposited on the lung tissue of smokers with emphysema, and smoke-exposed mice. Together, these findings suggest a critical role for C3a through autocrine/paracrine induction of C3aR in the pathogenesis of cigarette smoke-induced sterile inflammation and provide new therapeutic targets for the treatment of emphysema.

Injectable biomaterials for the treatment of stress urinary incontinence: their potential and pitfalls as urethral bulking agents.

Injectable urethral bulking agents composed of synthetic and biological biomaterials are minimally invasive treatment options for stress urinary incontinence (SUI). The development of an ideal urethral bulking agent remains challenging because of clinical concerns over biocompatibility and durability. Herein, the mechanical and biological features of injectable urethral biomaterials are investigated, with particular emphasis on their future potential as primary and secondary treatment options for SUI. A literature search for English language publications using the two online databases was performed. Keywords included "stress urinary incontinence", "urethral bulking agent" and "injectable biomaterial". A total of 98 articles were analysed, of which 45 were suitable for review based on clinical relevance and importance of content. Injectable biomaterials are associated with a lower cure rate and fewer postoperative complications than open surgery for SUI. They are frequently reserved as secondary treatment options for patients unwilling or medically unfit to undergo surgery. Glutaraldehyde cross-linked bovine collagen remains the most commonly injected biomaterial and has a cure rate of up to 53 %. Important clinical features of an injectable biomaterial are durability, biocompatibility and ease of administration, but achieving these requirements is challenging. In carefully selected patients, injectable biomaterials are feasible alternatives to open surgical procedures as primary and secondary treatment options for SUI. In future, higher cure rates may be feasible as researchers investigate alternative biomaterials and more targeted injection techniques for treating SUI.

Nodal presentation of seminoma.

We report a 38 year old male with metastatic seminoma in an inguinal lymph node and regression of the primary testis tumour with a past history of orchiopexy--an extremely rare occurrence.

Multistrain influenza protection induced by a nanoparticulate mucosal immunotherapeutic.

All commercial influenza vaccines elicit antibody responses that protect against seasonal infection, but this approach is limited by the need for annual vaccine reformulation that precludes efficient responses against epidemic and pandemic disease. In this study we describe a novel vaccination approach in which a nanoparticulate, liposome-based agent containing short, highly conserved influenza-derived peptides is delivered to the respiratory tract to elicit potent innate and selective T cell-based adaptive immune responses. Prepared without virus-specific peptides, mucosal immunostimulatory therapeutic (MIT) provided robust, but short-lived, protection against multiple, highly lethal strains of influenza in mice of diverse genetic backgrounds. MIT prepared with three highly conserved epitopes that elicited virus-specific memory T-cell responses but not neutralizing antibodies, termed MITpep, provided equivalent, but more durable, protection relative to MIT. Alveolar macrophages were more important than dendritic cells in determining the protective efficacy of MIT, which induced both canonical and non-canonical antiviral immune pathways. Through activation of airway mucosal innate and highly specific T-cell responses, MIT and MITpep represent novel approaches to antiviral protection that offer the possibility of universal protection against epidemic and pandemic influenza.

Link between allergic asthma and airway mucosal infection suggested by proteinase-secreting household fungi.

Active fungal proteinases are powerful allergens that induce experimental allergic lung disease strongly resembling atopic asthma, but the precise relationship between proteinases and asthma remains unknown. Here, we analyzed dust collected from the homes of asthmatic children for the presence and sources of active proteinases to further explore the relationship between active proteinases, atopy, and asthma. Active proteinases were present in all houses and many were derived from fungi, especially Aspergillus niger. Proteinase-active dust extracts were alone insufficient to initiate asthma-like disease in mice, but conidia of A. niger readily established a contained airway mucosal infection, allergic lung disease, and atopy to an innocuous bystander antigen. Proteinase produced by A. niger enhanced fungal clearance from lung and was required for robust allergic disease. Interleukin 13 (IL-13) and IL-5 were required for optimal clearance of lung fungal infection and eosinophils showed potent anti-fungal activity in vitro. Thus, asthma and atopy may both represent a protective response against contained airway infection due to ubiquitous proteinase-producing fungi.

An assessment of the long-term health outcome of renal transplant recipients in Ireland.

BACKGROUND: Renal transplantation remains the preferred method of renal replacement therapy in terms of patient survival, quality of life and cost. However, patients have a high risk of complications ranging from rejection episodes, infection and cancer, amongst others. AIMS AND METHODS: In this study, we sought to determine the long-term health outcomes and preventive health measures undertaken for the 1,536 living renal transplant patients in Ireland using a self-reported questionnaire. Outcomes were divided into categories, namely, general health information, allograft-related information, immunosuppression-related complications and preventive health measures. RESULTS: The results demonstrate a high rate of cardiovascular, neoplastic and infectious complications in our transplant patients. Moreover, preventive health measures are often not undertaken by patients and lifestyle choices can be poor. CONCLUSIONS: This study highlights the work needed by the transplantation community to improve patient education, adjust immunosuppression where necessary and aggressively manage patient risk factors.

Phagocytosis mediated by Yersinia invasin induces collagenase-1 expression in rabbit synovial fibroblasts through a proinflammatory cascade.

We show that the interaction of the Yersinia surface protein, invasin, with rabbit synovial fibroblasts mediates bead phagocytosis and induces expression of interleukin 1alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha) and MMP-1/collagenase-1 (CL-1). Presentation of invasin as a ligand on the surface of 4.5 microm beads induced phagocytosis and increased CL-1 expression 20-fold after 24 hours. By contrast, presentation of invasin as a spreading substrate did not induce CL-1 expression. CL-1 induction following phagocytosis of invasin-coated beads was mediated by a mechanism dependent on high-affinity binding to beta1 integrins and the function of the small GTPase RhoA. Expression of a function-perturbing mutant, RhoAN19, abrogated bead-induced CL-1 expression. RhoA activation coupled bead phagocytosis with signal transduction because expression of constitutively active mutant RhoV14 was sufficient to trigger CL-1 expression. The signal-transduction cascade elicited by bead phagocytosis triggered NFkappaB activation, stimulating a proinflammatory cellular response with transient increases in TNF-alpha production that peaked at 2 hours and induction of IL-1alpha that was sustained for at least 10 hours. Inhibition of IL-1alpha function by blocking antibodies or IL-1 receptor antagonist showed that IL-1alpha is the autocrine intermediary for subsequent CL-1 induction.

Effects of methylenedioxymethamphetamine on noradrenaline-evoked contractions of rat right ventricle and small mesenteric artery.

We have compared the effects of methylenedioxymethamphetamine (MDMA) and cocaine on contractions to noradrenaline in 1 Hz paced rat right ventricular strips, and in rat small mesenteric artery and aorta. Noradrenaline increased the force of contraction of 1 Hz paced ventricular strips with a pD(2) (-log EC(50)) of 5.64+/-0.07. Both cocaine (10 microM) and MDMA (10 microM) significantly increased the potency of noradrenaline to 6.31+/-0.11 and 6.42+/-0.13, respectively. However, in the presence of cocaine (10 microM) which increased the potency of noradrenaline to 6.78+/-0.15, MDMA (10 microM) no longer increased the potency of noradrenaline (pD(2) of 6.78+/-0.32). Likewise, following chemical sympathectomy, MDMA failed to increase the potency of noradrenaline. The potency of the agonist isoprenaline, which is not a substrate for the noradrenaline transporter, was not increased by either cocaine or MDMA. In rat small mesenteric artery, but not aorta, MDMA and cocaine significantly increased the potency of noradrenaline, but in the presence of cocaine, MDMA had no further effect. Hence, MDMA shares with cocaine an ability to potentiate the actions of noradrenaline, an action in the case of MDMA which may involve competitive blockade of the noradrenaline transporter, rather than simply displacement of noradrenaline. Since cocaine is linked to an increased incidence of myocardial infarction, these results may have implications in terms of cardiac morbidity of MDMA.

Induction and regulation of the IgE response.

Immunoglobulin E (IgE) is believed to be one of the major mediators of immediate hypersensitivity reactions that underlie atopic conditions such as urticaria, seasonal allergy, asthma and anaphylaxis. Factors that control IgE production are therefore essential to the pathogenesis of these important afflictions. But a complete understanding of this topic is lacking, while new data have raised questions regarding the precise role of IgE in atopic disease. Evolving concepts of IgE production and elimination are likely to clarify the importance of IgE in health and disease.

Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change.

Integrin-mediated reorganization of cell shape leads to an altered cellular phenotype. Disruption of the actin cytoskeleton, initiated by binding of soluble antibody to alpha5beta1 integrin, led to increased expression of the collagenase-1 gene in rabbit synovial fibroblasts. Activation of the guanosine triphosphate-binding protein Rac1, which was downstream of the integrin, was necessary for this process, and expression of activated Rac1 was sufficient to increase expression of collagenase-1. Rac1 activation generated reactive oxygen species that were essential for nuclear factor kappa B-dependent transcriptional regulation of interleukin-1alpha, which, in an autocrine manner, induced collagenase-1 gene expression. Remodeling of the extracellular matrix and consequent alterations of integrin-mediated adhesion and cytoarchitecture are central to development, wound healing, inflammation, and malignant disease. The resulting activation of Rac1 may lead to altered gene regulation and alterations in cellular morphogenesis, migration, and invasion.

Assessment of operative risk for patients with advanced lung disease.

Increasingly, patients with advanced lung disease are being offered operative procedures. The assessment of the perioperative risk of these patients must include not only the assessment of their lung disease, but the assessment of the patient's cardiovascular disease, their age, and their other medical problems. Knowledge of the stress of particular surgical procedures is also of importance in risk assessment, and is addressed in this article.

Soluble transforming growth factor-alpha is present in the pulmonary edema fluid of patients with acute lung injury.

Recent in vivo and in vitro experimental evidence indicates that transforming growth factor-alpha (TGF-alpha) is an important growth factor in the process of recovery and remodeling that occurs after acute lung injury. However, there are very little clinical data on TGF-alpha in patients with acute lung injury. Therefore, the purpose of this study was to determine if TGF-alpha is present in biologically significant concentrations in the pulmonary edema fluid from patients with acute lung injury, and to determine if the presence of TGF-alpha is specific for acute lung injury by including control patients with hydrostatic edema. Using an enzyme-linked immunosorbent assay, plasma and pulmonary edema fluid TGF-alpha levels were measured in 43 patients (34 with increased permeability edema, nine with hydrostatic edema). TGF-alpha was detected in 24 of 34 patients (71%) with increased permeability pulmonary edema (range, 0.035 to 2.57 ng/mL) compared with only two of nine patients with hydrostatic edema (p < 0.05). TGF-alpha was not detected in any plasma samples. These concentrations of TGF-alpha in pulmonary edema fluid have potent in vivo and in vitro effects on alveolar epithelial sodium transport and alveolar epithelial cell motility. In conclusion, biologically relevant concentrations of soluble TGF-alpha are present in the pulmonary edema fluid on day 1 of patients with acute lung injury, a remarkable finding with important implications for the repair and resolution of acute lung injury, particularly since TGF-alpha was detected so early in the course of acute lung injury.

Soluble and insoluble fibronectin increases alveolar epithelial wound healing in vitro.

Adhesive interactions between cells and extracellular matrix proteins are important in cell attachment, migration, and proliferation. The present work defines the role of fibronectin (soluble and insoluble) compared with type I and type IV collagen on in vitro alveolar epithelial wound healing. Repeated video microscopy experiments demonstrated that the half-time of wound closure was decreased in the presence of soluble fibronectin (6.6 +/- 2.1 vs. 17.4 +/- 0.8 h in serum-free medium, P < 0.05). Video microscopy, electron microscopy, and vinculin distribution demonstrated the contribution of two main events during the repair process: the migration of epithelial cell sheets and the spreading of the cells. During the wound healing, the internuclear distance between two adjacent cells at the migrating edge of the wound was significantly increased 10 h after wounding in the presence of soluble fibronectin (67 +/- 3.0 vs. 45 +/- 1.5 microns in serum-free medium, P < 0.05), indicating that cell spreading is involved as part of the mechanism for wound closure. Compared with type I and type IV collagen, insoluble fibronectin was the most potent stimulus for alveolar type II cell motility and wound healing in the absence of other serum factors. These results demonstrate that alveolar epithelial wound healing can be modulated in vitro by the composition of the extracellular matrix, an effect that may be mediated by changes in cell shape.

Transforming growth factor-alpha enhances alveolar epithelial cell repair in a new in vitro model.

Alveolar epithelial type II cells are essential for regenerating an intact alveolar barrier after destruction of type I cells in vivo. The first objective of these experimental studies was to develop an in vitro model to quantify alveolar epithelial cell wound repair. The second objective was to investigate mechanisms of alveolar epithelial cell wound healing by studying the effects of serum and transforming growth factor-alpha (TGF-alpha) on wound closure. Primary cultures of rat alveolar type II cells were prepared by standard methods and grown to form confluent monolayers in 48 h. Then a wound was made by denuding an area (mean initial area of 2.1 +/- 0.6 mm2) of the monolayer. Re-epithelialization of the denuded area over time in the presence or absence of serum was measured using quantitative measurements from time-lapse video microscopy. The half time of wound healing was significantly enhanced in the presence of serum compared with serum-free conditions (2.4 +/- 0.2 vs. 17.4 +/- 0.8 h, P < 0.001). We then tested the hypothesis that TGF-alpha is an important growth factor for stimulating wound repair of alveolar epithelial cells. Exogenous addition of TGF-alpha in serum-free medium resulted in a significantly more rapid wound closure, and, furthermore, the addition of a monoclonal antibody to TGF-alpha in the presence of serum significantly decreased fourfold the rate of wound closure. Measurement of internuclear cell distance confirmed that both cell motility and cell spreading were responsible for closure of the wound. These data demonstrate that 1) the mechanisms of alveolar cell repair can be studied in vitro and that 2) TGF-alpha is a potent growth factor that enhances in vitro alveolar epithelial cell wound closure.

The effect of salt water on alveolar epithelial barrier function.

The effect of hyperosmolar fluid aspiration (seawater) on lung fluid balance has not been well studied. Therefore, the effect of this clinically relevant form of acute lung injury on the alveolar epithelial and lung endothelial barriers was examined in ventilated, anesthetized rabbits. Seawater (4 ml/kg body weight, 881 +/- 29 mOsm/kg) with 3 microCi of 125I-albumin was instilled into the lower trachea of ventilated, anesthetized rabbits. Osmotic equilibration with plasma was completed within the first 5 min after seawater instillation. In parallel with the osmotic equilibration of the seawater in the air spaces, there was a 3-fold dilution of the alveolar protein tracer 125I-albumin, indicating an initial large (300%) increase in alveolar fluid volume. There was a marked decline in arterial oxygenation at the same time that the alveolar fluid volume markedly increased. The initial dilution of the alveolar protein tracer was followed by a progressive increase in the alveolar protein tracer concentration that continued until 6 h after seawater instillation. As the alveolar protein tracer concentrated, arterial oxygenation improved, indicting net alveolar liquid clearance. There was only a mild increase in the epithelial and endothelial permeability to protein within the first 2 h after seawater instillation. Thus, a large osmotically induced increase in alveolar fluid volume with severe pulmonary edema did not cause sustained injury to the endothelial or epithelial barriers of the lung. In fact, normal alveolar liquid clearance occurred, indicating the resistance of the epithelial barrier to hyperosmolar injury as well as its capacity to rapidly reabsorb excess alveolar fluid.