Acute Diffuse Lung Injury Research Articles

STING-deficiency in lung resident mesenchymal stromal cells contributes to the alleviation of LPS-induced lung injury

Acute respiratory distress syndrome (ARDS) is characterized by acute diffuse inflammatory lung injury with a high mortality rate. Mesenchymal stromal cells (MSC) are pluripotent adult cells that can be extracted from a variety of tissues, including the lung. Lung-resident MSC (LR-MSC) located around vascular vessels and act as important regulators of lung homeostasis, regulating the balance between lung injury and repair processes. LR-MSC support the integrity of lung tissue by modulating immune responses and releasing trophic factors. Studies have reported that the STING pathway is involved in the progression of lung injury inflammation, but the specific mechanism is unclear. In this study, we found that STING deficiency could ameliorate lipopolysaccharides (LPS)-induced acute lung injury, STING knockout (STING KO) LR-MSC had an enhanced treatment effect on acute lung injury. STING depletion protected LR-MSC from LPS-induced apoptosis. RNA-sequencing and Western blot results showed that STING KO LR-MSC expressed higher levels of MSC immunoregulatory molecules, such as Igfbp4, Icam1, Hgf and Cox2, than WT LR-MSC. This study highlights that LR-MSC have a therapeutic role in acute lung injury, and we demonstrate that STING deficiency can enhance the immunomodulatory function of LR-MSC in controlling lung inflammation. Thus, STING can be used as an intervention target to enhance the therapeutic effect of MSC.

Acute Respiratory Distress Syndrome: A Case Report and Review on Diagnosis and Novel Interventions in Management

Acute respiratory distress syndrome is a type of acute diffuse lung injury, frequently brought on by sepsis, trauma, and severe pulmonary infections and continues to be one of the major causes of morbidity and mortality in critically ill patients, despite the constantly involving advancements. The management strategies have constantly evolved with a wide array of ventilation strategies, conservative fluid management, neuromuscular blockade. As we move into the post pandemic Era, the mortality rate due to ARDS continues to remain high hence improving patient outcomes is the primary goal of the various treatment approaches. The two most effective techniques are still prone ventilation and lung protection ventilation. In this report we aim to present the case of a 30-year old female who has undergone left lobectomy in childhood and presents to the clinic with palpitations, fever, shortness of breath and spasmodic cough with phlegm. The workup included chest Xray, CT scan, arterial blood gas with electrolytes, echocardiography and urinanalysis. Based on clinical and imaging findings, the diagnosis of acute respiratory distress syndrome was made. Against the background of intensive treatment, the patient’s condition improved to some extent, with positive dynamics. Lung protective ventilation, prone ventilation, high frequency oscillatory ventilation among many other novel interventions and futuristic direction of ARDS with mesenchymal stromal cells and Ulinastatin, a urinary glycoprotein and protease inhibitor provides a ray of hope in the management of this acute condition. Keywords: Acute respiratory distress syndrome; hypoplasia; lung ventilation; prone ventilation; mesenchymal stem cells; ulinastatin

Acute respiratory distress syndrome heterogeneity and the septic ARDS subgroup.

Acute respiratory distress syndrome (ARDS) is an acute diffuse inflammatory lung injury characterized by the damage of alveolar epithelial cells and pulmonary capillary endothelial cells. It is mainly manifested by non-cardiogenic pulmonary edema, resulting from intrapulmonary and extrapulmonary risk factors. ARDS is often accompanied by immune system disturbance, both locally in the lungs and systemically. As a common heterogeneous disease in critical care medicine, researchers are often faced with the failure of clinical trials. Latent class analysis had been used to compensate for poor outcomes and found that targeted treatment after subgrouping contribute to ARDS therapy. The subphenotype of ARDS caused by sepsis has garnered attention due to its refractory nature and detrimental consequences. Sepsis stands as the most predominant extrapulmonary cause of ARDS, accounting for approximately 32% of ARDS cases. Studies indicate that sepsis-induced ARDS tends to be more severe than ARDS caused by other factors, leading to poorer prognosis and higher mortality rate. This comprehensive review delves into the immunological mechanisms of sepsis-ARDS, the heterogeneity of ARDS and existing research on targeted treatments, aiming to providing mechanism understanding and exploring ideas for accurate treatment of ARDS or sepsis-ARDS.

Research progress of transcription activating factor 3 in regulating the alveolar macrophages in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) refers to acute diffuse lung injury caused by a variety of intrapulmonary and/or extrapulmonary factors such as infection and trauma. Uncontrolled inflammatory response is the main pathological feature. Different functional states of alveolar macrophages have different effects on inflammatory response. Transcription activating factor 3 (ATF3) is a fast response gene in the early stage of stress. In recent years, it has been found that ATF3 plays an important role in regulating the inflammatory response of ARDS by regulating the function of macrophages. This paper reviews the regulatory effects of ATF3 on alveolar macrophage polarization, autophagy and endoplasmic reticulum stress and its effects on the inflammatory process of ARDS, aiming to provide a new research direction for the prevention and treatment of ARDS.

Recent advances in understanding acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is characterized by acute diffuse lung injury, which results in increased pulmonary vascular permeability and loss of aerated lung tissue. This causes bilateral opacity consistent with pulmonary edema, hypoxemia, increased venous admixture, and decreased lung compliance such that patients with ARDS need supportive care in the intensive care unit to maintain oxygenation and prevent adverse outcomes. Recently, advances in understanding the underlying pathophysiology of ARDS led to new approaches in managing these patients. In this review, we want to focus on recent scientific evidence in the field of ARDS research and discuss promising new developments in the treatment of this disease.

Prevalence of Respiratory Distress Syndrome in Neonates

Background: Acute respiratory distress syndrome is defined as acute diffuse inflammatory lung injury causing increased pulmonary vascular permeability with increased lung weight, loss of aerated lung tissues leading to hypoxemia and bilateral radiographic opacities associated with increased venous admixture, increased physiological dead space and decreased lung compliance. Aim of work: to determine the prevalence rates of respiratory distress syndrome (RDS) in neonates in King Abdulaziz Hospital, Taif city, Saudi Arabia and to find out the most important causes of RDS in preterm babies in Taif city. Methods: a cross-sectional questionnaire based study carried out in Saudi Arabia, Taif city, King Abdulaziz Hospital from January to June 2016 (6 months period) on preterm neonates. Results: 57.1% of newborn were male gender and 42.9% were female, 4.4% of babies were extreme preterm, 86.5% were preterm, 4.4% were late preterm and 4.7% were full term, the prevalence rate of RDS in newborn was 54.7% in the 6 months of this study. Conclusion: RDS is one of the major problems among newborns and a major reason for increased morbidity and mortality among infants. Preterm babies are the main risk factor for development of RDS. Mother’s illnesses, especially hypertension and Diabetes are very strong risk factors for the disease in preterm babies. Cesarean delivery, especially in preterm babies and male gender stays other important risk factors for RDS.

Treatment of the acute respiratory distress syndrome with Keratinocyte growth factor: another failure to account

Acute respiratory distress syndrome (ARDS) is a life-threatening clinical syndrome defined as an acute and severe diffuse lung injury of known origin (1). The mortality rate for ARDS is still high, although it has decreased in the last decades (2). Current treatments are only supportive and there is no effective therapy interfering with the molecular basis of ARDS (3,4): in fact, despite extensive research, almost all promising potential therapies have proven unsuccessful in clinical trials. This is also the case of a randomized, double-blind, placebo-controlled phase II trial evaluating the keratinocyte growth factor (KGF) for the treatment of the ARDS (KARE trial), which has been recently published in the Lancet Respiratory Medicine (5).

Research progress of biomarkers of acute respiratory distress syndrome

ARDS is a type of acute diffuse lung injury, characterized by inflammation leading to increased pulmonary vascular permeability and loss of aerated lung tissue, the clinical manifestations are refractory hypoxia, progressive respiratory distress and non cardiac pulmonary edema.ARDS mortality rate is very high, especially in patients with severe ARDS, about 27%-45%. In order to improve diagnostic specificity, a revised definition was published in JAMA in 2012, but no new biomarkers or parameters were adopted.Along with the progress in understanding the pathophysiology of ARDS, a variety of humoral factors by inflammation and molecules derived from injured tissues or activated cells may be potential biomarkers for clinical.

Interferon-Gamma Signaling in the Pathogenesis of Idiopathic Pneumonia Syndrome Following Allogeneic Bone Marrow Transplantation

Idiopathic pneumonia syndrome (IPS) is a life-threatening acute noninfectious diffuse lung injury occurring after allogeneic bone marrow transplantation (BMT). We have recently shown that absence of STAT1 signaling in recipient APC leads to accelerated Graft Versus Host Disease (GVHD) and Transplant-associated mortality and morbidity after lethal irradiation in fully MHC-mismatched allogeneic or in non-irradiated P→F1 BMT models. We now addressed the impact of recipient Type II interferon signaling on the development of lung injury after allogeneic BMT using a non-irradiated P→F1 model. 1x107 BMCs plus 2.5x107 SPCs from C57BL/6 (B6) mice were i.v. injected into IFNγR-deficient CB6F1 (F1.GRKO) or CB6F1 wild type (WT) mice. F1.GRKO recipients had significantly reduced survival (MST 32 days post-BMT vs. not reached p<0.001, Log-rank test). Pulmonary function tests were performed 3 weeks post-BMT on anaesthetized mice that were tracheotomized and mechanically ventilated using a computer-controlled animal ventilator (Flexivent, SCIREQ). Static compliance was derived from plateau pressure measurements between total lung capacity and functional residual capacity, and broadband forced oscillations were used to determine airway resistance at baseline and following increasing doses of methacholine (3.1, 12.5 and 50 mg/ml). Static compliance and inspiratory capacity were reduced in F1.GRKO recipients when compared with WT mice (p<0.01). In addition, airway resistance, both at baseline and in response to methacholine, was increased in the KO recipient mice (p<0.05). Histopathology was evaluated on H&E, Trichrome and PAS stained lung sections to assess for inflammation, fibrosis and mucus hyperplasia, respectively. Lungs from the KO mice showed increased interstitial inflammation involving bronchioles, vasculature and parenchyma (pathology index 10 vs 1; p<0.001), fibrosis (fibrosis score 2.8 vs 0.15; p<0.05) and a trend for mucus hyperplasia/metaplasia. To further evaluate the cellular mediators of the observed lung injury, we assessed the cellular composition of the bronchioalveolar lavage fluid (BAL) at day 30 post-BMT. We observed a 10-fold increase in the total cell number of the BAL in F1.GRKO recipient mice compared to WT mice (4x105 vs.4x104, p<0.01); the majority of the cells in the BAL from wild type mice were macrophages/monocytes, while neutrophils predominated in the F1.GRKO mice. Importantly, more than 50% of the CD45+ BAL cells were donor derived in the F1.GRKO recipients, compared to only 10% in the wild type recipients. Furthermore, the absolute cell number of donor CD4+ and CD8+ cells in the knockout mice significantly outnumbered that in their wild type counterparts (p<0.01). Thus, our results suggest that absence of recipient IFN-γR signaling promotes accumulation and/or trafficking of donor neutrophils and T cells to the lungs. To better understand the underlying mechanisms of enhanced infiltration of donor cells in the lungs of IFNγR-/- mice, the activation, proliferation, and differentiation status of donor lymphocytes were assessed by Flowcytometry after BMT. In line with the lung infiltration, there was significantly increased donor cell engraftment in PBMC, spleen, lymph nodes, and bone marrow in F1.GRKO recipients (all with p<0.01); Moreover, there were also significantly increased activation (measured as CD44high CD62Llow cells), Th1 and Tc1 differentiation of donor CD4 and CD8 cells (p<0.01). Furthermore, enhanced Th17 differentiation, but reduced Foxp3+ Treg cell differentiation was noticed. Interestigly, we observed significantly lower PD-L1 expression on recipient APC in the F1.GRKO mice compared to wild type mice, suggesting that absence of PD-L1 expression may contribute to reduced contraction of activated donor T cells. Interestingly, in line with these findings we also observed significantly reduced PD-L1 expression when single cell suspension from lung tissues were analyzed by flow. Reduced PD-L1 expression was observed on both recipient CD45+, and CD45- cells in F1.GRKO when tested on day 22 post-BMT, meanwhile there was no difference in PD-L1 expression pattern in the cells isolated from small intestine. These results suggest that IFN-γ induced PD-L1 expression on hematopoietic and non-hematopoietic cells in the lung may be of significance in protecting recipients against acute donor-cell mediated lung injury and IPS. DisclosuresLentzsch:Celgene: Membership on an entity's Board of Directors or advisory committees; Axiom: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Optimal support techniques when providing mechanical ventilation to patients with acute respiratory distress syndrome.

Adult respiratory distress syndrome (ARDS) is a type of acute diffuse lung injury characterized by severe inflammation, increased pulmonary vascular permeability and a loss of aerated lung tissue. The effects of high fraction of inspired oxygen (FiO2 ) include oxygen toxicity manifested by damage to the lung parenchyma in the acute phase of lung injury. There is still a high mortality rate among this group of patients, so clinically sensitive evidence-based interventions are paramount to maximize survival chances during critical care. The aim of this article is to explore the current opinion concerning optimal mechanical ventilation support techniques for patients with acute respiratory distress syndrome. A literature search of clinical trials and observation studies, reviews, discussion papers, meta-analyses and clinical guidelines written in English up to 2015, derived from the databases of Scopus, CINAHL, Cochrane Library databases and PubMed was conducted. Low tidal volume, pressure limitation and prone positioning in severe ARDS patients appear to be of some benefit. More research is required and further development and use of standardized protocols is an important strategy for reducing practice variations across disciplines, as well as giving clear guidelines to nurses practising in critical care. There is also evidence that this syndrome is under-diagnosed and the utilization of lung protective ventilation is still variable. It is important that nurses have underlying knowledge of both aetiology of ARDS and ventilation management, and that they monitor patients very closely. The adoption of a low tidal ventilation protocol, which is based on quality evidence guidelines, the value of rescue therapies and patient observation practices in the overall patient management, and the need to place emphasis on long-term patient outcomes, all these emerge as key factors for consideration and future research. However, there is also a need for more research that would explore the unique contribution of nurses in the management of this patient group, as it is difficult to discern this in the current literature.

Distribution of influenza A (H5N1) virus and pathological lesions in major organ tissues of experimentally infected rhesus macaques

To investigate the pathological changes and viral invasion in the main organs of rhesus macaques after experimental infection with H5N1 virus. The rhesus macaques were infected with H5N1 virus (AF148678/ACGoose/Guangdong/11961H5N1) by nasal inoculation under anesthesia. One rhesus macaque was killed respectively at 1, 3, 6, 14 days after infection. The pathologic changes of the main organs were observed using HE staining and the characteristics of the viral invasion in the body were analyzed using viral isolation, RT-PCR andimmunohistochemistry. The influenza virus replicated only in the lung tissues characterized by diffuse alveolar damage in the infected rhesus macaques, mainly involving alveolar epithelial cells and pulmonary macrophages. The pathological changes showed 3 phases including exudative inflammation, hyperplasia and fibrosis. Extra-pulmonary organs also showed different degree of pathological changes such as degeneration and necrosis, but virus was not isolated in the corresponding organs. Acute diffuse lung injury was a central part of the pathogenesis in H5N1 avian influenza virus infection. The lung was the main target organ in H5N1 viral infection, and H5N1 virus cannot replicate in other organs, which may be one of the obstacles to H5N1 viral transmission from person to person.

A New Definition for the Acute Respiratory Distress Syndrome

Similar to other syndromes, patients are defined as having acute respiratory distress syndrome (ARDS) when they meet prespecified diagnostic criteria. These criteria have evolved over time, having gained and lost complexity, but the core principles have remained remarkably similar over the past 45 years. The specific diagnostic criteria allow clinicians and investigators to reliably identify patients with the syndrome of ARDS. ARDS is a form of acute diffuse lung injury occurring in patients with a predisposing risk factor. Lung injury is characterized by inflammation leading to increased endothelial and epithelial permeability and loss of aerated lung tissue resulting in hypoxemia and bilateral radiographic opacities on chest radiography. Additional physiological derangements include increased venous admixture and physiological dead space along with decreased respiratory system compliance. The corresponding pathological findings are lung edema, inflammation, hyaline membranes, and alveolar hemorrhage (i.e., diffuse alveolar damage). This article discusses the evolution of the definition of ARDS to the new Berlin definition of ARDS proposed in 2012 and its novel iterative refinement.

Protective effects of recombinant human erythropoietin on acute lung injury induced by sepsis in rats

Objective To investigate the protective effects of recombinant human erythropoietin (rHuEPO) on acute lung injury (ALI) induced by lipopolysaccharide (LPS).Methods Fourty-five rats were randomly (random number) assigned to three groups,namely control group,model group,and rHuEPO group.ALI was induced by intravenous injection of LPS (6 mg/kg).The rHuEPO (5000 U/kg) was injected intravenously into rats 60 min before LPS challenge.The general status of rats was observed.Twelve hours after modeling,the rats were sacrificed and the tissue samples including lung tissue and blood were collected.PaO2,PaCO2,pH,the lung wet/dry weight ratio,plasma cytokines [interleukin (IL) IL-6 and tumor necrosis factor-alpha (TNF-α)],and inducible nitric oxide synthase (iNOS) were detected.Cytokines were assayed with ELISA method.Pathological changes of lung tissues were observed under light microscope and transmission electron microscopy.Results (1) Compared with the control group,PaO2,pH in the model group and in the rHuEPO group were significantly lower (P ＜ 0.05),and PaCO2 were significantly higher (P ＜ 0.05).Compared with the model group,PaO2,pH in the rHuEPO group were significantly higher (P ＜ 0.05),and PaCO2 were significantly lower (P ＜ 0.05).(2) Compared with the control group,the W/D weight ratio of lung tissues in the model group and the rHuEPO group was significantly higher (P ＜ 0.05).Compared with the model group,the W/D weight ratio of lung tissues in the rHuEPO group significantly lower (P ＜ 0.05).(3) The levels of TNF-o,IL-6 and iNOS in serum of rats in the control group were lower than those in the model group and the rHuEPO group (P ＜0.01).The serum levels of TNF-α,IL-6 and iNOS of rats in the rHuEPO group were significantly lower compared with the model group (P ＜ 0.01).(4) The light microscopy and the transmission electron microscopy showed the model group had histopathologic changes with acute diffuse lung injury manifested by intra-alveolar hemorrhage,exudate,inflammatory cells infiltration,Ⅰ type and Ⅱ type epithelial cell necrosis and detachment,and the pathological changes of lung tissue in the rHuEPO group were not as serious as those in the LPS group,showing only a little inflammatory cells infiltration of focal alveoli.Conclusions Recombinant human erythropoietin can inhibit the genesis of TNF-α,IL-6 and iNOS in serum,modifying the inflammatory response and providing protective effects against acute lung injury induced by sepsis. Key words: Recombinant human erythropoietin ; Lipopolysaccharides ; Sepsis ; Acute lung injury

321: Il-17 Is a Mediator of Bleomycin-Induced Acute Lung Injury in Mice

Murine lung T cell receptor (TCR) γδ T cells are intraepithelial cells critical in regulating inflammation. We previously demonstrated in TCR δ−/− mice that bleomycin (blm) induced acute diffuse lung injury (ALI) is associated with delayed epithelial regeneration (1). As TCR γδ T cells are a major source of IL-17 production, we tested if IL-17 knockout (ko) mice would demonstrate similar patterns of Blm-induced ALI.

DNA Repair Proteins as Molecular Therapeutics for Oxidative and Alkylating Lung Injury

Endogenous and environmental oxidation is increasingly becoming an important factor associated with numerous disorders in both children and adults. The lung is particularly prone to oxidation, as the gas exchange organ is continuously exposed to a great deal of airborne oxidants. Lung oxidation-induced toxicity is a critical clinical problem that is currently lacking cure. For example, treatment for acute respiratory distress syndrome (ARDS), a common type of acute diffuse lung injury, is strictly supportive. Alkylating chemotherapeutics and many methyl chemicals can cause acute or chronic lung injury, which is also difficult to treat. Many new approaches are being tried to improve the treatment of lung oxidation and alkylation; one of these is the use of DNA repair proteins, such as base excision repair proteins that are largely involved in repairing DNA damage caused by oxidation and alkylation. Recent advances have revealed their promising potential for treating oxidation toxicity. Here we discuss discoveries that have led to this possibility, including pioneering research into the cellular signaling transduction and molecular mechanisms of DNA repair proteins. In conclusion, when combined with other therapeutic measures such as anti-oxidant chemicals and enzymes, DNA repair proteins may have great potential for treating acute and chronic lung toxicity induced by oxidation and alkylation.

Sequential appearance of inflammatory mediators in rat bronchoalveolar lavage fluid after oleic acid-induced lung injury.

The oleic acid (OA) model of rat lung injury was originally developed as a model of fat embolism syndrome. A single intravenous dose of pure OA causes an acute diffuse lung injury, which, in its initial stages, histologically and physiologically resembles human ARDS. Rat lungs acutely injured by intravenous OA manifest increased levels of ICAM-1 within 30-60 min. This study shows that human umbilical vein endothelial cells (HUVEC) can be used in a bioassay to reveal some of the adhesion molecule stimulating activities present in bronchoalveolar lavage fluid (BALF) from post-OA-injected rats: (1) There is an as yet unidentified ICAM-1 and ELAM (E Selectin) inducing activity in BALF within 15 min of OA injection that is not TNF alpha; there is very little measurable tumor necrosis factor-alpha (TNF alpha) in 15 min BALF (BALF15). (2) BALF15 also stimulates cultured macrophage derived from BALF of normal rat lungs to produce TNF alpha. (3) By 60 min after OA injection, 50-75% of the ICAM-1 and ELAM inducing activity in BALF (BALF60) is TNF alpha; BALF60 contains about 250-280 pg/mL TNF alpha. The other 25-50% adhesion molecule-inducing activity in BALF60 is unidentified. (4) The ICAM-1-inducing activity of pure TNF alpha was equal to that of BALF60 containing equivalent concentrations of TNF alpha. The ELAM inducing activity of pure TNF alpha, however, was about 1/2 that of BALF60 containing equivalent concentrations of TNF alpha. The time courses for ICAM and ELAM stimulation with pure TNF alpha or BALF60 containing equivalent levels of TNF alpha were the same. The identity of the mediators in BALF15 and BALF60 that are not TNF alpha and the mechanisms by which OA injection stimulates cytokine production remain to be elucidated.

Elastin fiber analysis in acute diffuse lung injury caused by smoke inhalation.

The evaluation of various techniques to diagnose or exclude ventilator-associated bacterial pneumonia has been a focus of much research. One such technique involves elastin fiber detection. It has been inferred from previous work that 40% potassium hydroxide preparations of respiratory secretions that demonstrate elastin fibers have a 100% specificity in diagnosing bacterial pneumonia in intubated, mechanically ventilated patients without acute diffuse lung injury. The purpose of this investigation was to ascertain if elastin fibers might be detected in respiratory secretions in acute, diffuse lung injury in the absence of pneumonia (i.e., assess specificity). An animal model using a standardized smoke inhalation protocol to cause acute, diffuse lung injury was used. Respiratory secretions collected from the endotracheal tubes from eight sheep that underwent the standardized smoke inhalation protocol and were examined with 40% potassium hydroxide. Histologic data were obtained from autopsy to diagnose or exclude lung injury and pneumonia. We found six (false) positive elastin fiber preparations in the absence of histologic pneumonia. Specificity was 0.25. We concluded that seeing these results, given a true specificity of 0.99 inferred from previous work, is highly improbable with a probability of 2.74 x 10(-7). Thus, elastin fiber analysis is likely to be highly nonspecific for diagnosing pneumonia in the setting of acute diffuse lung injury.

Natural surfactant and hyperoxic lung injury in primates. II. Morphometric analyses

Diffuse lung injury is accompanied by low compliance and hypoxemia with histological evidence of endothelial and alveolar epithelial cell disruption. The histological effects of treatment of an acute diffuse lung injury with a natural surfactant product were evaluated in a primate model because surfactant function and content have been shown to be abnormal in diffuse lung injury in both animals and humans. Ten baboons were ventilated with 100% O2 for 96 h, and 5 were given an aerosol of natural porcine surfactant. Physiological and biochemical measurements of the effects of hyperoxia and surfactant treatment are presented in a companion paper. After O2 exposure, lungs were fixed and processed for quantitative electron microscopy. The responses to O2 included epithelial and endothelial cell injuries, interstitial edema, and inflammation. The hyperoxic animals treated with surfactant were compared with the untreated animals; the treatments altered neutrophil distribution, fibroblast proliferation, and changes in the volumes of type I epithelial cells and endothelial cells. Surfactant-treated animals also had decreased lamellar body volume density in type II epithelial cells and preservation of endothelial cell integrity. These changes suggest complex effects of natural surfactant on the pulmonary response to hyperoxia, including protection against epithelial and endothelial cell destruction as well as significant interstitial inflammation and fibroblast proliferation. We conclude that natural surfactant treatment of hyperoxic lung injury in primates resulted in partial protection of epithelial and endothelial cells but also increased the accumulation of fibroblasts in the lung.

Acute lung injury. Pathogenesis of intraalveolar fibrosis.

In patients dying with acute lung injury, interstitial mesenchymal cells migrate into the airspace where they replicate and deposit connective tissue. We therefore hypothesized that peptides capable of promoting mesenchymal cell migration and replication would be present in the alveolar airspace. To examine this hypothesis, patients with severe acute diffuse lung injury (n = 26) underwent bronchoalveolar lavage. Acutely ill patients without lung injury served as controls (n = 12). Recovered effluent was examined for mesenchymal cell growth-promoting and migration-promoting activity. Lavage cell supernates from both patients and controls were devoid of bioactivity. However, substantial growth-promoting and migration-promoting activity was present in lavage fluid from nearly every patient, whereas little or none was present in fluid from controls. Characterization of the bioactivity indicated a significant proportion consisted of three peptides related to PDGF: (a) a 14-kD peptide that shared with PDGF several biophysical, biochemical, receptor-binding, and antigenic properties; (b) a 29-kD peptide that appeared identical to PDGF of platelet origin; and (c) a 38-kD peptide that was biophysically and antigenically similar to PDGF. These data indicate that peptide moieties are present in the airspace of patients after acute lung injury that can signal mesenchymal cell migration and replication.

Interactions of granulocytes with the lungs.

Under normal conditions, there is a sizeable pool of marginated granulocytes in the lung circulation which is in dynamic equilibrium with the circulating granulocyte pool. The number of granulocytes in the lungs' microcirculation may depend on pulmonary blood flow or biochemical interactions between granulocytes and pulmonary vascular endothelium, or both. There is some evidence that normal lung function may be affected by granulocytes. Several acute and chronic diseases may result, at least in part, from interactions of granulocytes with the lungs. Acute diffuse lung injury (adult respiratory distress syndrome) is characterized by diffuse pulmonary inflammation, and, in animal models, some of the lung dysfunction depends on the presence of granulocytes. Bronchoconstriction and airway hyperreactivity, characteristic of asthma, may be influenced by granulocyte-generated products of arachidonic acid. Granulocyte-derived proteases and oxidants may contribute to the pathogenesis of pulmonary emphysema and may affect connective tissue synthesis in interstitial pulmonary fibrosis. There is some evidence suggesting a connection between granulocytes and chronic pulmonary hypertension. The fact that some interventions which cause pulmonary leukostasis do not cause severe, persistent lung injury indicates that as yet unknown factors may determine whether interactions of granulocytes with the lungs are benign or pathological. Such factors could include the generation of humoral substances, and metabolites of arachidonic acid are particularly interesting in this regard. Research related to interactions of granulocytes with the lungs suggests strongly that such interactions are integral to the pathogenesis of several lung diseases. Understanding those diseases will require further basic studies of granulocyte behavior and the modes of communication between cells intrinsic to the lung and granulocytes.