Fibroblasts consist of heterogeneous subpopulations that have distinct roles in fibrotic responses. Previously we reported enhanced proliferation in response to fibrogenic growth factors and selective activation of latent transforming growth factor (TGF)-␤ in fibroblasts lacking cell surface expression of Thy-1 glycoprotein, suggesting that Thy-1 modulates the fibrogenic potential of fibroblasts. Here we report that compared to controls Thy-1؊/؊ C57BL/6 mice displayed more severe histopathological lung fibrosis, greater accumulation of lung collagen, and increased TGF-␤ activation in the lungs 14 days after intratracheal bleomycin. The majority of cells demonstrating TGF-␤ activation and myofibroblast differentiation in bleomycin-induced lesions were Thy-1-negative. Histological sections from patients with idiopathic pulmonary fibrosis demonstrated absent Thy-1 staining within fibroblastic foci. Normal lung fibroblasts, in both mice and humans, were predominantly Thy-1-positive. The fibrogenic cytokines interleukin-1 and tumor necrosis factor-␣ induced loss of fibroblast Thy-1 surface expression in vitro, which was associated with Thy-1 shedding, Smad phosphorylation, and myofibroblast differentiation. These results suggest that fibrogenic injury promotes loss of lung fibroblast Thy-1 expression, resulting in enhanced fibrogenesis. (Am J Pathol 2005, 167:365-379) Idiopathic pulmonary fibrosis (IPF), with its histopathological signature of usual interstitial pneumonia (UIP), is a paradigmatic, but as yet primarily enigmatic example of uncontrolled fibroproliferation. IPF is remarkable for its insidious onset, dramatic histopathological and pathophysiological derangements, and relentless progression to death regardless of treatment. The etiology of IPF, and the factors that direct its dismal outcome, remain the subject of intense investigation.1 Fibroblasts are the cellular sine qua non of fibrosis in most tissues, and the histopathology of IPF underscores this observation. The histopathological feature most clearly correlated with outcome is the presence in lung of fibroblastic foci of young connective tissue, the presence of which portends death within months.2 Fibroblastic foci seem to represent the fibroproliferative leading edge of the heterogeneous areas of scarring in IPF.3-5 The myofibroblasts within these foci are clearly dysregulated in their proliferative and matrix-productive function, yet the origin of these cells, and the factors that lead to their accumulation and persistence, are unknown.Fibroblasts in most tissues are heterogeneous with respect to size, secretory profile, and surface markers. Fibroblasts within a fibrogenic milieu clearly differ from those in normal tissues. In particular, fibroblasts isolated from lungs with active fibrotic disease have increased proliferative capacity, are capable of anchorage-independent growth, and are morphologically distinct. 6 -8 Furthermore, differences among subsets of normal fibroblasts have been identified on the basis of surface markers, cytoskeleta...

-The alveolar fibrinolytic system is altered in acute lung injury (ALI). Levels of the fibrinolytic protease inhibitor, plasminogen activator inhibitor-1 (PAI-1), are too low in bronchoalveolar lavage to address its prognostic significance. This study was performed to assess whether PAI-1 antigen in undiluted pulmonary edema fluid levels can identify patients with ALI and predict their outcome. PAI-1 antigen levels in both plasma and edema fluid were higher in ALI compared with hydrostatic edema, and edema fluid PAI-1 values identified those with ALI with high sensitivity and specificity. Both the high plasma and edema fluid PAI-1 antigen values were associated with a higher mortality rate and fewer days of unassisted ventilation in patients with ALI. Differences in PAI-1 activity were concordant with levels of PAI-1 antigen. Although the fibrinderived alveolar D-dimer levels were strikingly similar in both groups, ALI patients had a higher relative proportion of D-monomer. In conclusion, PAI-1 levels in edema fluid and plasma identify those with ALI that have a poor prognosis. The data indicate that fibrin turnover in early ALI is a consequence of a rapid fibrinogen influx and fractional fibrinolytic inhibition.fibrinolysis; prognosis CURRENT ESTIMATES INDICATE that the incidence of acute lung injury (ALI) is 20-75 per 100,000 persons, with a mortality rate of 20-60% (48). Prior studies that have attempted to identify prognostic markers in bronchoalveolar lavage (BAL) fluid obtained from patients with ALI in the first several days after intubation have met with only modest success (7,8,15,37,38). Several obstacles exist in identifying valuable and reliable prognostic markers in ALI. For instance, it is clear that the lung inflammation evolves rapidly in ALI, making the timing of the analysis crucial. Second, there are both soluble activators and inhibitors for numerous cytokines/chemokines in the inflammatory milieu. Third, the BAL procedure itself dilutes the alveolar contents 100-fold, making it difficult to quantify potentially useful markers of ALI. Finally, the heterogeneity of underlying diseases and choice of control groups add to the difficulty in extrapolating the findings to disease pathobiology. We have overcome some of these obstacles by utilizing undiluted pulmonary edema fluid, not BAL fluid, that was obtained from patients with clinical ALI and well-defined hydrostatic pulmonary edema (HYDRO) controls within hours of intubation and initiation of mechanical ventilation.ALI is characterized by the deposition of fibrin in the alveolar space. Deposition of fibrin in the alveolar space is the net result of an alteration in the balance of coagulation and fibrinolytic proteases [plasmin and urokinase type plasminogen activators (u-PA)] and antiproteases [plasminogen activator inhibitor-1 (PAI-1) and ␣ 2 -antiplasmin] and the availability of plasmaderived fibrinogen (31,35). Upon fibrinogen influx into the alveolar compartment, coagulation/fibrinolysis proteases/antiproteases act to generate insoluble cr...

OBJECTIVES: To determine the proportion of infections caused by extended-spectrum ß-lactamase (ESBL)–producing Klebsiella or Escherichia coli Gram-negative organisms in the pediatric intensive care unit (PICU), and to identify risk factors for these infections. METHODS: A retrospective, single-center chart review of patients admitted to a PICU in a 5-year period with infections caused by Klebsiella species or E coli was completed. Data collected include demographics, length of stay, outcome, and relevant risk factors previously defined in the literature. RESULTS: A total of 110 isolates were cultured from 94 patients. A total of 53% of the isolates were E coli, and the remainder were Klebsiella subspecies. Of the 110 isolates, 13 isolates (11.8%) in 7 patients were ESBL positive. The ESBL-producing isolates were equally distributed amongE coli and Klebsiella and were primarily cultured from tracheal aspirates. Most of the ESBL-positive isolates (9 of 13; 69%) were cultured from patients who received ceftazidime and/or cefotaxime in the preceding 30 days. Patients infected with E coli had higher PRISM 1 scores and were more likely to have a Foley catheter, whereas infections with Klebsiella were more common in mechanically ventilated males. Although not statistically significant, 80% of patients who were infected with non–ESBL-producing organisms survived to hospital discharge versus 57% of those infected with ESBL-producing E coli and Klebsiella. CONCLUSIONS: Almost 12% of E coli and Klebsiella isolates in this patient population tested positive for ESBL production. ESBL production was equally distributed between E coli and Klebsiella species. These organisms were cultured from 7% of the study patients. As reported in previous studies, patients infected with ESBL-producing organisms most often had received prior cephalosporins and had a longer length of stay in the PICU.

The CPP method appears to be safe, although this feasibility study does not establish that the CPP therapy is superior to ICP therapy.

Methylene blue (MB) is a medication commonly used to treat methemoglobinemia, reducing methemoglobin to hemoglobin. A novel use of MB, as detailed here, is in the treatment of refractory hypotension. A number of reports have detailed use of MB for this purpose in adults, but few data in pediatrics. A 22-month-old girl with Noonan syndrome, biventricular hypertrophic cardiomyopathy, and chronic positive pressure ventilation developed shock with tachycardia, hypotension, and fever after 3 days of diarrhea. She was critically ill, with warm extremities, bounding pulses, and brisk capillary refill. Laboratory tests revealed metabolic acidosis, low mixed venous oxygen saturation, and leukocytosis with bandemia. Treatment of severe septic shock was initiated with fluid resuscitation, inotropic support, sedation, and paralysis. She remained hypotensive despite norepinephrine at 0.7 mg/kg per minute, dopamine at 20 mg/kg per minute, and vasopressin at 0.04 U/kg per hour. Her vasoplegic shock worsened, despite aggressive conventional therapy. Intravenous MB was initiated, with a loading dose of 1 mg/kg followed by a continuous infusion at 0.25 mg/kg per hour. Upon initiation of MB, her systolic blood pressure increased by 33 points (40% increase), and diastolic blood pressure increased by 20 points (46% increase). She was able to wean off all inotropes quickly after initiation of MB. MB should be considered in the setting of refractory vasoplegic shock in the PICU.