Preoperative nomogram to predict posthepatectomy liver failure.

BACKGROUND AND OBJECTIVES: Posthepatectomy liver failure (PHLF) is associated with significant morbidity and mortality. However, it is often difficult to predict the risk of PHLF in an individual patient. We aimed to develop a preoperative nomogram to predict PHLF and allow better risk stratification before surgery. METHODS: Data for patients undergoing a partial or major hepatectomy were extracted from the hepatectomy-specific NSQIP database for years 2014-2016. Data set from 2017 was used for validation. Patients with Grade B/C liver failure were compared with patients with no liver failure. RESULTS: A total of 10 808 patients from 2014-2016 data set were included. Of these, 316 patients (2.9%) developed Grade B/C PHLF. In the multivariable model consisting of preoperative variables, the following were predictive of Grade B/C PHLF (all p < 0.05): male gender, biliary stent, neoadjuvant therapy, viral hepatitis B or C, concurrent resections, biliary reconstruction, low sodium, and low albumin (model c statistic-0.78). This model was used to construct a nomogram. In the 2017 validation cohort of 4367 patients the nomogram again demonstrated good c-statistic (0.78). CONCLUSIONS: Our nomogram provides patient-specific probabilities for PHLF, and is easy to use. This is a valuable tool that can be utilized for preoperative patient counseling and selection.

Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation.

The cholinergic anti-inflammatory reflex (CAIR) represents an important homeostatic regulatory mechanism for sensing and controlling the body's response to inflammatory stimuli. Vagovagal reflexes are an integral component of CAIR whose anti-inflammatory effects are mediated by acetylcholine (ACh) acting at α7 nicotinic acetylcholine receptors (α7nAChR) located on cells of the immune system. Recently, it is appreciated that CAIR and α7nAChR also participate in the control of metabolic homeostasis. This has led to the understanding that defective vagovagal reflex circuitry underlying CAIR might explain the coexistence of obesity, diabetes, and inflammation in the metabolic syndrome. Thus, there is renewed interest in the α7nAChR that mediates CAIR, particularly from the standpoint of therapeutics. Of special note is the recent finding that α7nAChR agonist GTS-21 acts at L-cells of the distal intestine to stimulate the release of two glucoregulatory and anorexigenic hormones: glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Furthermore, α7nAChR agonist PNU 282987 exerts trophic factor-like actions to support pancreatic ß-cell survival under conditions of stress resembling diabetes. This review provides an overview of α7nAChR function as it pertains to CAIR, vagovagal reflexes, and metabolic homeostasis. We also consider the possible usefulness of α7nAChR agonists for treatment of obesity, diabetes, and inflammation.

A systematic review and meta-analysis of predictors of recurrence in patients with Solid Pseudopapillary Tumors of the Pancreas.

BACKGROUND: The recurrence rates and predictors of recurrence in patients with Solid Pseudopapillary tumors (SPT) are unclear, which makes it challenging to determine the duration of follow-up. The aim of the current study was to perform a systematic review and meta-analysis to determine the recurrence rates and pathologic factors associated with recurrence in patients with SPT. METHODS: A PubMed, Scopus, and Web of Science search was conducted to identify studies of SPT published during the last 15 years: (09/2002-09/2017). Studies reporting on patients with SPT and follow-up of >5 years were included. The search strategy was conducted per 2009 PRISMA guidelines. RESULTS: A total of 103 studies reporting on 2599 non-metastatic SPT patients were identified. Sixty-nine patients (2.6%) developed recurrence during follow-up. Pooled estimates from studies with a sample size >20 (N = 33) noted an overall recurrence rate of 2% (95% CI 1-2%). Male gender (OR 1.960), positive lymph nodes (OR 11.9), R1 margins (OR 11.1), and LVI (OR 5.5), were associated with a significantly (all p < 0.05) increased risk of recurrence. CONCLUSION: Current meta-analysis suggests that only 2% of patients with SPT experience recurrence after resection. These data will guide the treating physicians and patients regarding recurrence rates and help identify patients at increased risk of recurrence during follow-up.

Review and Update on the Role of Peritoneal Cytology in the Treatment of Gastric Cancer.

BACKGROUND: Positive peritoneal cytology (Cyt+) even in the absence of macroscopic disease is associated with poor prognosis in patients with gastric cancer and deemed as M1 disease. Recent years have seen advancements in the evaluation strategies for peritoneal washings and management of patients with Cyt+. The aim of this review was to describe the newest paradigms in the management of patients with gastric cancer who have Cyt+ without macroscopic peritoneal metastases. METHODS: A comprehensive literature review was performed to identify studies on the management of gastric cancer and thereby to summarize relevant information on the accuracy of various diagnostic tests and controversies involved in the treatment of patients with Cyt+. RESULTS: Although conventional cytology remains the standard technique for assessment of peritoneal washings, it is limited by low sensitivity. The role of immunohistochemistry and molecular techniques for the assessment of peritoneal washings is evolving. Although systemic chemotherapy remains the standard of care for patients with Cyt+ disease, the role of gastrectomy, intraperitoneal chemotherapy, extensive intraperitoneal saline lavage, and hyperthermic intraperitoneal chemotherapy is being evaluated. CONCLUSIONS: Clinical decision-making in patients with Cyt+ remains controversial given the seemingly technical resectable albeit biologically unresectable or aggressive disease that portends an overall poor prognosis. Current management strategies are evolving, and further studies are needed to develop an optimal treatment strategy for these patients.

Protective effects of glutathione on oxidative injury induced by hydrogen peroxide in intestinal epithelial cells.

BACKGROUND: Reactive oxygen species are increased in multiple gastrointestinal diseases and contribute to their pathogenesis. glutathione (GSH) is an antioxidant that helps to prevent reactive oxygen species-mediated mucosal damage. This study examines the mechanisms by which GSH attenuates hydrogen peroxide (H2O2)-induced injury in intestinal epithelial cells. METHODS: IEC-6 cells were cultured and treated with H2O2 ± GSH. Inflammation was measured by nuclear factor kappa-B (NF-κB) P65 expression, NF-κB nuclear translocation, iκBα phosphorylation, and interleukin 1 beta secretion. Terminal deoxynucleotidyl transferase-mediated UTP end-labeling staining and cleaved caspase-3 were used to assess apoptosis. The role of P38 mitogen-activated protein kinase (P38 MAPK) signaling was examined using the P38 MAPK agonist U46619 and inhibitor SB203580 in H2O2 and GSH-treated cells. Phosphorylated and total P38 MAPKs and cleaved caspase-3 were measured by Western blot. Data are means ± standard deviation, statistical significance P < 0.05 by student's t-test, or one-way analysis of variance. RESULTS: Pretreatment with GSH attenuates the activation of NF-κB and P38 MAPK signaling pathways by H2O2. GSH also decreased H2O2-mediated increases in interleukin 1 beta secretion, cleaved caspase-3 activation, and apoptosis in IEC-6 cells. SB203580 attenuated the increase in apoptosis and cleaved caspase-3 in H2O2-treated cells. The increase in apoptotic index and cleaved caspase-3 observed in U46619-treated cells was also diminished by GSH. CONCLUSIONS: GSH appears to ameliorate oxidative injury in intestinal epithelial cells by attenuating H2O2-mediated activation of NF-κB and P38 MAPK signaling pathways that regulate intestinal inflammation and apoptosis.

Emergence Agitation and Anesthetic Considerations in the Management of Patients With Post-Traumatic Stress Disorder: A Report of Two Cases and a Review of the Literature.

Post-traumatic stress disorder (PTSD) is a psychological disturbance resulting from exposure to a traumatic experience that lasts more than one month. PTSD in the United States has a lifetime prevalence of 3.4% to 26.9% in civilians and 7.7% to 17.0% in military veterans. Emergence agitation (EA) and emergence delirium (ED) are known phenomena in the postanesthetic period. PTSD is closely associated with EA following anesthesia. In addition, EA in patients with PTSD can be severe and challenging to manage. EA is a risk to both patients and healthcare workers. Furthermore, EA has been shown to increase the overall risk of postoperative delirium and complications. Currently, studies on the anesthetic management of patients with PTSD are scarce and limited to case reports. Here, we present a summary of several important published case reports and a brief review of the literature regarding the anesthetic management of PTSD and EA to aid in managing patients with PTSD. In addition, we present two cases of successful EA prevention in patients with severe PTSD. From our review of the literature and the successful prevention of EA in our patients with severe PTSD, we conclude that there is an increased need for overall awareness among anesthesia and perioperative care providers of the effect of PTSD on EA. Anesthesia providers should aim to include as many management recommendations as possible and avoid possible triggers of EA via a multidisciplinary approach. Multiple pharmacological agents have been used for the anesthetic management of PTSD with varying results. Of the agents studied, dexmedetomidine has been found to be the most consistently beneficial.

Thyroid paraganglioma in a patient with a history of carotid and vagal paraganglioma: metastatic or primary tumor?

Paragangliomas (PGs) are extremely rare multicentric neoplasms. Hereditary or familial PGs are associated with germline mutations in succinate dehydrogenase genes, seen in one-third of cases. Primary PGs of the thyroid are uncommon neuroendocrine neoplasms that account for 0.012% of all head and neck lesions. Although majority of these tumors are solitary, familial PGs are associated with synchronous tumors (carotid/vagal). We report an interesting case of primary thyroid PG in a patient with a previous history of a right carotid body, right vagal PGs and positive familial history, confining the differential diagnosis to recurrent lesions, which is the most common occurrence or new primary or a metastatic lesion. However, long interval and surgical anatomy suggests the diagnosis to be a primary lesion. In conclusion, although these lesions present multicentrically present at varying intervals, their occurrence at anatomically distinct sites should raise the concern for a new primary PG.

Perioperative Evaluation of Infective Endocarditis Via Multimodality Imaging for the Surgical Management of Aortic Root Abscess.

Infective endocarditis (IE) is an infection of the endothelium of the heart, that typically affects heart valves. While echocardiography remains crucial in the diagnosis and management of IE, multimodality cardiac imaging helps obtain additional information for the management of complex cases. Alternative imaging modalities such as computed tomography (CT), computed tomography angiography (CTA), and magnetic resonance imaging (MRI) are playing an increasing role in the diagnosis and management of IE, especially for patients with prosthetic valve endocarditis (PVE). Here we present a case of a 60-year-old Caucasian male who was diagnosed with IE, complicated by aortic root abscess, and multiorgan failure. In this challenging case, multimodality cardiac imaging helped in the precise understanding of the extent of endocarditis, cannulation strategy, and direct the course of the surgical procedure that resulted in successful patient management.

Prognosis of duodenal gangliocytic paraganglioma with lymph node metastasis: is follow-up >5 years required?

Gangliocytic paragangliomas (GP) are rare tumors encountered exclusively in the second portion of the duodenum. Duodenal gangliocytic paraganglioma (DGP) belongs to a subclass of neuroendocrine neoplasms, characterized with unique histologic features of carcinoid tumor, paraganglioma and ganglioneuromas. According to the recent World Health Organization classification of gastrointestinal neuroendocrine tumors (NETs), there is a debate to classify them either as low-grade NETs or as an independent entity. There are a few reports of regional lymph node (LN) metastasis that could argue DGP as a true neoplasm. However, majority of them had a benign course, raising the question of whether long-term follow-up is required. We report a case of a retroperitoneal LN involvement by metastatic GP and additionally performed a systematic review of the literature to determine the optimal follow-up, since no guidelines exist for this rare entity.

Sparstolonin B: A Unique Anti-Inflammatory Agent.

Toll-like receptors are transmembrane proteins which sense and transmit infectious and inflammatory responses to the cells expressing them. Therapeutic strategies for the blockade of excessive Toll-like receptor signaling are being actively pursued for several diseases. Recently, Sparstolonin B, isolated from Chinese herb, which suppresses selectively Toll-like receptors has been studied in various inflammatory models. The objective of this review is to summarize the current literature regarding the use of Sparstolonin B in various in vitro and in vivo studies and to provide an overview regarding the potential use of this agent in different inflammatory diseases. Additionally, the current knowledge regarding the role of Toll-like receptors in inflammatory disease and the usage of various Toll-like receptor antagonists will be summarized. Based on our review, we believe Sparstolonin B could serve as a potential therapeutic agent for treatment of Toll-like receptor-mediated inflammatory disorders.

High-grade malignant pancreatic neoplasm with sarcomatoid features.

Sarcomatoid carcinoma is a rare and aggressive form that occur at diverse locations in the body such as upper respiratory tract, upper and lower digestive tracts, genitourinary tract, breast and thyroid glands. However, its occurrence in pancreas has been rarely reported. Sarcomatoid carcinoma of pancreas (SCP) is a high-grade epithelial malignancy composed predominantly of spindle cells often having features suggestive of epithelial derivation without features indicative of a specific line of mesenchymal differentiation. Its pathogenesis has not been elucidated. Microscopically, SCP comprises mostly anaplastic cells and is strikingly sarcoma-like in appearance. Confirmation of this disease is often based on the pathological diagnosis. We report a case that was incidentally found after a CT was done for worsening chronic back pain and the patient was found to have a pancreatic mass and a liver lesion. Endoscopic ultrasound (EUS)-guided liver biopsy revealed high grade malignant pancreatic neoplasm with sarcomatoid features. Further CT chest revealed bilateral lung nodules and PET scan revealed prominent bony metastases within vertebral bodies at L1, L2, and L3. The patient refused definitive treatment and succumbed to illness within 3 months.

Poorly differentiated signet ring cell carcinoma of pancreas masquerading as chronic pancreatitis.

Pancreatic cancer is typically arises in the context of inflammation, and a surrounding area of pancreatitis is often present within the tumor microenvironment. Signet ring cell carcinoma (SRCC) is a rare variant of pancreatic adenocarcinoma. Pathologically, it presents either as single cells or loose clusters masquerading in the background of pancreatitis. Sampling of these inflammatory cells during biopsy can result in the incorrect diagnosis of pancreatitis. We report a case of SRCC of the pancreas which the diagnosis of cancer was delayed because multiple biopsies revealed only inflammatory changes with no obvious evidence of malignancy. This case highlights the fact that negative results with endoscopic ultrasound fine needle aspiration in SRCC can be misleading. A cancer diagnosis should still be considered despite findings of inflammatory pancreatitis if the clinical presentation is concerning for cancer (mass on CT scan).

Surfactant Proteins-A and -D Attenuate LPS-Induced Apoptosis in Primary Intestinal Epithelial Cells (IECs).

INTRODUCTION: SP-A/D KO mice with sepsis demonstrate more severe lung, kidney, and gut injury/apoptosis than WT controls. We hypothesize SP-A and SP-D directly regulate lipopolysaccharide (LPS)-induced P38 mitogen-activated protein kinase (MAPK) activation and gut apoptosis during sepsis. METHODS: Primary IECs were established from SP-A/D KO or C57BL/6 WT mice, stimulated with LPS and harvested at 24 h. IECs from WT mice were treated with SP-A, SP-D, or vehicle for 20 h, then LPS for 24 h. Apoptosis, cleaved caspase-3 levels and the ratio of BAX/Bcl-2 were assayed. The role of P38 MAPK was examined using the P38 MAPK-agonist U46619 and inhibitor SB203580 in LPS-treated cells. p-P38 MAPK/t-P38 MAPK, TLR4, and CD14 were measured by Western Blot. RESULTS: LPS-induced apoptosis, caspase-3 levels, BAX/Bcl-2, and p-P38/t-P38 MAPK were increased in SP-A/D KO IECs. SP-A and SP-D attenuate LPS-induced increase in apoptosis, cleaved caspase-3, BAX/Bcl-2, and p-P38/t-P38 MAPK in WT IECs. U46619 increased apoptosis, caspase-3, and BAX/Bcl-2 in IECs which was attenuated by SP-A/D. SB203580 attenuates the LPS-induced increase in apoptosis, caspase-3, and BAX/Bcl-2 in WT IECs. Addition of SP-A or SP-D to SB203580 completely ameliorates LPS-induced apoptosis. The LPS-induced increase in TLR4 and CD14 expression is greater in IECs from SP-A/D KO mice and treatment of WT IECs with SP-A or SP-D prevents the LPS-induced increase in TLR4 and CD14. CONCLUSIONS: SP-A and SP-D attenuate LPS-induced increases in apoptosis, caspase-3, and BAX/Bcl-2 in IECs. Attenuation of LPS-induced activation of TLR4 and P38 MAPK signaling pathways represents potential mechanisms for the protective effects of SP-A/D on apoptosis.

Nonoperative Management May Be a Viable Approach to Plexiform Neurofibroma of the Porta Hepatis in Patients with Neurofibromatosis-1.

BACKGROUND: Plexiform neurofibroma (PNF) in the porta hepatis (PH) is an unusual manifestation of neurofibromatosis-1 (NF-1). Resection is often recommended given the risk of malignant transformation. We encountered a challenging case in clinical practice which prompted us to report our findings and perform a systematic review on the management of these tumors. METHODS: We reported the case of a 31-year-old woman with NF-1 and PNF of the PH. PRISMA 2009 guidelines were followed for systematic review. RESULTS: Our patient was found to have unresectable disease at exploration. After >5 years of follow-up, she continued to have stable disease on imaging. We identified 12 studies/case reports including 10 adult and 6 pediatric patients with PNF of PH. None of the 7 adult patients with NF-1 and PNF of PH underwent a successful tumor resection. All pediatric patients were managed with surveillance alone. All but one pediatric patient had NF-1. None of the reported cases of PNF of PH had malignant transformation. CONCLUSION: Our findings suggest that PNFs of PH in the setting of NF-1 are often unresectable and may have an indolent course. Surveillance alone may be a reasonable option in some patients; however, further studies are needed.

Osteoclast-like giant cell tumor of the pancreas-an unusual presentation in a patient with large mantle cell lymphoma.

Osteoclast-like giant cell tumor of the pancreas is very rare. We report a 78-year-old male who was previously treated for large mantle cell lymphoma, was found to have an increased uptake in a peri-pancreatic node from his restaging PET scan. Endoscopic ultrasound-directed fine-needle aspiration of the mass and lymph node revealed an undifferentiated carcinoma with osteoclast-like giant cells. Osteoclast-like giant cell tumors of the pancreas are frequently found to be unresectable at diagnosis due to their large size (>5 cm). In our patient, due to its small size (<3 cm) sub-total pancreatectomy was performed. Three years from the surgery, the patient is doing well without recurrence. This case report intends to increase provider awareness that in the setting of new pancreatic lesions in a patient with previous history of lymphoma, a high index of suspicion for a primary pancreatic lesion should be included in the differential diagnosis.

α7 Nicotinic Acetylcholine Receptor Regulates the Function and Viability of L Cells.

Enteroendocrine L cells secrete the incretin hormone glucagon-like peptide-1 (GLP-1), and they also express the α7 nicotinic acetylcholine receptor (α7nAChR), which may regulate GLP-1 secretion. Here, GTS-21, a selective α7nAChR agonist, was used to examine the effect of α7nAChR activation in L-cell lines, mouse intestinal primary cell cultures, and C57BL/6 mice. GTS-21 stimulated GLP-1 secretion in vitro, and this effect was attenuated by an α7nAChR antagonist or by α7nAChR-specific small interfering RNA. Under in vitro cell culture conditions of glucotoxicity, GTS-21 restored GLP-1 secretion and improved L-cell viability while also acting in vivo to raise levels of circulating GLP-1 in mice. To assess potential signaling mechanisms underlying these actions of GTS-21, we first monitored Ca2+, cAMP, and phosphatidylinositol 3-kinase (PI3K) activity. As expected for a GLP-1 secretagogue promoting Ca2+ influx through α7nAChR cation channels, [Ca2+]i increased in response to GTS-21, but [cAMP]i was unchanged. Surprisingly, pharmacological inhibition of growth factor signaling pathways revealed that GTS-21 also acts on the PI3K-protein kinase B-mammalian target of rapamycin pathway to promote L-cell viability. Moreover, the Ca2+ chelator BAPTA-AM counteracted GTS-21‒stimulated PI3K activity, thereby indicating unexpected crosstalk of L-cell Ca2+ and growth factor signaling pathways. Collectively, these data demonstrate that α7nAChR activation enhances GLP-1 secretion by increasing levels of cytosolic Ca2+ while also revealing Ca2+- and PI3K-dependent processes of α7nAChR activation that promote L-cell survival.

Enteral administration of bacteria fermented formula in newborn piglets: A high fidelity model for necrotizing enterocolitis (NEC).

OBJECTIVE: To develop an animal model which replicates neonatal NEC and characterizes the importance of bacterial fermentation of formula and short chain fatty acids (SCFAs) in its pathogenesis. BACKGROUND: NEC is a severe form of intestinal inflammation in preterm neonates and current models do not reproduce the human condition. METHODS: Three groups of newborn piglets: Formula alone (FO), Bacteria alone (E.coli: BO) and E.coli-fermented formula (FF) were anesthetized, instrumented and underwent post-pyloric injection of formula, bacteria or fermented-formula. SCFA levels were measured by gas chromatography-mass spectrometry. At 6 h bowel appearance was assessed, histologic and molecular analysis of intestine were performed. Gut inflammation (p65 NF-κB, TLR4, TNF-α, IL-1ß), apoptosis (cleaved caspase-3, BAX, apoptosis) and tight junction proteins (claudin-2, occludin) were measured. RESULTS: SCFAs were increased in FF. Small bowel from FF piglet's demonstrated inflammation, coagulative necrosis and pneumatosis resembling human NEC. Histologic gut injury (injury score, mast cell activation) were increased by Bacteria, but more severe in FF piglets. Intestinal expression of p65 NF-κB, NF-κB activation, TNF-α and IL-1ß were increased in BO and markedly increased in the FF group (P<0.05 vs. FO). Intestine from Bacteria piglets demonstrated increased apoptotic index, pro-apoptotic protein expression and decreased tight junction proteins. These changes were more severe in FF piglets. CONCLUSIONS: Our piglet model demonstrates the findings of NEC in human neonates: systemic acidosis, intestinal inflammation, pneumatosis and portal venous gas. Bacteria alone can initiate intestinal inflammation, injury and apoptosis, but bacterial fermentation of formula generates SCFAs which contribute to the pathogenesis of NEC.

L-arginine attenuates Interleukin-1ß (IL-1ß) induced Nuclear Factor Kappa-Beta (NF-κB) activation in Caco-2 cells.

BACKGROUND: Specific nutrients like L-arginine (L-Arg) ameliorate intestinal inflammation, however the exact mechanisms of this effect are unclear. We hypothesized the anti-inflammatory effects of L-Arg require active transport and metabolism by inducible nitric oxide synthase (iNOS) to generate nitric oxide (NO). To test this hypothesis we examined the effects of L-Arg, L-Arg transport activity, NO production and iNOS inhibitor on IL-1ß-mediated NF-κB-activation in Caco-2 cells. METHODS: Caco-2 cells were cultured, transfected with a NF-κB promoter luciferase vector, incubated ± L-Arg, ± IL-1ß and luciferase activity was measured. Using siRNA we inhibited the L-Arg cationic amino acid transporter system y+ (CAT1) expression and examined its effects on L-Arg transport activity and IL-1ß-mediated NF-κB-activation. Finally, the effects of sodium nitroprusside (SNP, a NO donor) and Nω-nitro-L-arginine (NNA, an iNOS inhibitor) on IL-1ß-mediated NF-κB-activation were examined. RESULTS: IL-1ß increased NF-κB luciferase activity (8-fold) and NF-κB expression (mRNA and protein), both of these were significantly decreased by L-Arg. System y+ CAT1 siRNA decreased CAT1 expression, L-Arg transport activity and attenuated the inhibitory effects of L-Arg on NF- κB activity. SNP attenuated the IL-1ß-induced increase in NF-κB luciferase activity and expression, whereas NNA diminished the inhibitory effects of L-Arg on IL-1ß-inducible NF- κB luciferase activity. CONCLUSION: The inhibitory effects of L-Arg on IL-1ß-mediated NF-κB-activation in Caco-2 cells involve L-Arg transport activity by CAT1, regulation of IL-1ß-mediated increases in NF-κB expression, changes in iNOS expression and NO production. Our data suggest the inhibitory effects of L-Arg on NF-κB activation are mediated in part by iNOS since SNP preserves and NNA attenuates the effects of L-Arg on IL-1ß-mediated NF-κB-activation and expression.

The role of high airway pressure and dynamic strain on ventilator-induced lung injury in a heterogeneous acute lung injury model.

BACKGROUND: Acute respiratory distress syndrome causes a heterogeneous lung injury with normal and acutely injured lung tissue in the same lung. Improperly adjusted mechanical ventilation can exacerbate ARDS causing a secondary ventilator-induced lung injury (VILI). We hypothesized that a peak airway pressure of 40 cmH2O (static strain) alone would not cause additional injury in either the normal or acutely injured lung tissue unless combined with high tidal volume (dynamic strain). METHODS: Pigs were anesthetized, and heterogeneous acute lung injury (ALI) was created by Tween instillation via a bronchoscope to both diaphragmatic lung lobes. Tissue in all other lobes was normal. Airway pressure release ventilation was used to precisely regulate time and pressure at both inspiration and expiration. Animals were separated into two groups: (1) over-distension + high dynamic strain (OD + HDS, n = 6) and (2) over-distension + low dynamic strain (OD + LDS, n = 6). OD was caused by setting the inspiratory pressure at 40 cmH2O and dynamic strain was modified by changing the expiratory duration, which varied the tidal volume. Animals were ventilated for 6 h recording hemodynamics, lung function, and inflammatory mediators followed by an extensive necropsy. RESULTS: In normal tissue (NT), OD + LDS caused minimal histologic damage and a significant reduction in BALF total protein (p < 0.05) and MMP-9 activity (p < 0.05), as compared with OD + HDS. In acutely injured tissue (ALIT), OD + LDS resulted in reduced histologic injury and pulmonary edema (p < 0.05), as compared with OD + HDS. CONCLUSIONS: Both NT and ALIT are resistant to VILI caused by OD alone, but when combined with a HDS, significant tissue injury develops.