Biomedical subjects

Joseph P Lynch

Publications and source records attributed to Joseph P Lynch.

At least 19 recordsLinked to original sources

PubMed2007

IL-13 is pivotal in the fibro-obliterative process of bronchiolitis obliterans syndrome.

Acute allograft rejection is considered to be a predominately type 1 immune mediated response to the donor alloantigen. However, the type 2 immune mediated response has been implicated in multiple fibroproliferative diseases. Based on the fibro-obliterative lesion found during bronchiolitis obliterans syndrome (BOS), we hypothesized that the type 2 immune mediated response is involved in chronic lung allograft rejection. Specifically, whereas acute rejection is, in part, a type 1 immune response, chronic rejection is, in part, a type 2 immune response. We found the type 2 cytokine, IL-13, to be elevated and biologically active in human bronchoalveolar lavage fluid during BOS. Translational studies using a murine model of BOS demonstrated increased expression of IL-13 and its receptors that paralleled fibro-obliteration. In addition, in vivo neutralization of IL-13 reduced airway allograft matrix deposition and murine BOS, by a mechanism that was independent of IL-4. Furthermore, using IL-13Ralpha2(-/-) mice, we found increased fibro-obliteration. Moreover, anti-IL-13 therapy in combination with cyclosporin A had profound effects on reducing murine BOS. This supports the notion that IL-13 biological axis plays an important role during the pathogenesis of BOS independent of the IL-4 biological axis.

Animals↗

PubMed2006

The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung injury.

Mortality rates from acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) range from 30 to 65%. Although mechanical ventilation (MV) may delay mortality in critically ill patients with ALI/ARDS, it may also cause a lung injury that further promotes and perpetuates ALI/ARDS and multiorgan dysfunction syndrome (MODS). Recent studies have demonstrated that lung protective strategies of MV, as compared with the injurious strategy of conventional MV (CMV) can reduce absolute mortality rates during ALI/ARDS. The protective strategies limit tidal volumes and peak/plateau pressures while maximizing positive end-expiratory pressure. The injury to the lung by CMV is characterized histologically by edema, leukocyte extravasation, and endothelial and epithelial damage. Both human and animal studies suggest that alveolar cell deformation from CMV leads to the release of cytokines/chemokines which orchestrate the extravasation, activation, and recruitment of leukocytes, causing ventilator-associated lung injury (VALI) and ventilator-induced lung injury (VILI). Moreover, VALI/VILI can perpetuate the chronic inflammatory response during ALI/ARDS and MODS. This article explores the role of cytokines/chemokines during the pathogenesis of VALI/VILI.

Animals↗

PubMed2006

Overview of lung transplantation and criteria for selection of candidates.

Lung or heart-lung transplantation is a viable option for diverse end-stage pulmonary parenchymal or pulmonary vascular disorders. However, mortality associated with lung transplant (LT) is appreciable, with 3 and 5 year survival rates of approximately 60 and 50%, respectively. Thus LT is reserved for patients with life-threatening disease refractory to medical therapy. Four diagnoses (i.e., chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; cystic fibrosis; alpha-1-antitrypsin deficiency emphysema) account for approximately 80% of LT recipients; diverse interstitial and pulmonary vascular disorders account for the remaining cases. Given the potential morbidity and mortality associated with LT, the decision to refer patients for LT is difficult. Which patients are acceptable candidates for LT? What are the projected benefits of LT? What criteria should be used to estimate mortality with medical therapy alone? Given the uncertainty of waiting time, when should patients be listed for LT? Identifying appropriate candidates for LT and determining when to list for LT is determined by a risk analysis of the likelihood of mortality during the projected waiting period versus the likely mortality following LT. In this review, we discuss the major diseases treated with LT and the appropriate criteria for LT.

Cystic Fibrosis↗

PubMed2006

Inflammation and angiogenesis in fibrotic lung disease.

The pathogenesis of pulmonary fibrosis is poorly understood. Although inflammation has been presumed to have an important role in the development of fibrosis this has been questioned recently, particularly with regard to idiopathic pulmonary fibrosis (IPF). It is, however, increasingly recognized that the polarization of the inflammatory response toward a type 2 phenotype supports fibroproliferation. Increased attention has been on the role of noninflammatory structural cells such as the fibroblast, myofibroblast, epithelial cell, and endothelial cells. Furthermore, the origin of these cells appears to be multifactorial and includes resident cells, bone marrow-derived cells, and epithelial to mesenchymal transition. Increasing evidence supports the presence of vascular remodeling in fibrotic lung disease, although the precise role in the pathogenesis of fibrosis remains to be determined. Therefore, the pathogenesis of pulmonary fibrosis is complex and involves the interaction of multiple cell types and compartments within the lung.

Cell Proliferation↗

PubMed2006

Usual interstitial pneumonia.

Usual interstitial pneumonia (UIP) is a distinct histological lesion observed in idiopathic pulmonary fibrosis (IPF) but can be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high-resolution thin-section computed tomographic (CT) scans (provided the radiographic features are classical). Historically, patients labeled as "IPF" encompassed a group of disorders, including UIP as well as other idiopathic interstitial pneumonias that differ from UIP in prognosis and responsiveness to therapy. Current recommendations from international consensus statements restrict the term IPF to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of UIP have not been elucidated, but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of UIP is poor. Mean survival following diagnosis approximates 3 years. Current therapies are of unproven value. Corticosteroids or immunosuppressive agents have been most often used, but data affirming benefit are lacking. Lung transplantation is a viable option for patients failing medical therapy. This review discusses diagnostic criteria for UIP (both histopathological and radiographic), natural history and clinical course, and therapeutic approaches (both current and future).

Biomarkers↗

PubMed2006

Levofloxacin for the treatment of community-acquired pneumonia.

New respiratory fluoroquinolones (FQs), such as levofloxacin, offer many improved qualities over older agents, such as ciprofloxacin. These include retaining excellent Gram-negative bacilli activity, with improved Gram-positive activity. New FQ-like levofloxacin possesses greater bioavailabilty and a longer serum half-life compared with ciprofloxacin, allowing for once-daily dosing, which may improve patient adherence. The high bioavailability of levofloxacin allows for rapid step-down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve patient quality of life. Levofloxacin has been evaluated for the treatment of community-acquired pneumonia (CAP) in numerous randomized clinical trials. Most published studies have used the 500 mg dose, although more recent studies have investigated the 750 mg dose once daily. These trials demonstrate that levofloxacin is effective and safe for the treatment of CAP, displaying relatively mild adverse effects that are more or less comparable with ciprofloxacin. Levofloxacin has much to offer in terms of bacterial eradication, including for resistant respiratory pathogens. However, ciprofloxacin-resistant organisms are becoming more prevalent so prudence must be exercised when prescribing this agent.

Community-Acquired Infections↗

PubMed2006

Pharmacological therapy for Wegener's granulomatosis.

Wegener's granulomatosis (WG) is the most common pulmonary granulomatous vasculitis and was a uniformly fatal disease prior to the identification of efficacious pharmacological regimens. The pathogenesis of WG remains elusive but proteinase 3-specific anti-neutrophil cytoplasmic antibodies may be involved. Histologically, WG is defined by the triad of small vessel necrotising vasculitis, 'geographic' necrosis and granulomatous inflammation. Organ involvement characteristically includes the upper and lower respiratory tracts and kidney, but virtually any organ can be involved. The severity of the disease varies, ranging from asymptomatic disease to fulminant, fatal vasculitis. Similarly, the degree of organ involvement is highly variable; WG may be limited to a single organ (typically the lungs or upper respiratory tract), or may be systemic. Currently, a regimen consisting of daily cyclophosphamide and corticosteroids, which induces complete remission in the majority of patients, is considered standard therapy. Since approximately 50% of patients experience a relapse following discontinuation of therapy, alternative regimens designed to maintain remissions after using cyclophosphamide and corticosteroids are usually necessary. This 'induction maintenance' approach to treatment has emerged as a central premise in planning therapy for patients with WG.A number of trials have evaluated the efficacy of less toxic immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil) and antibacterials (i.e. cotrimoxazole [trimethoprim/sulfamethoxazole]) for treating patients with WG, resulting in the identification of effective alternative regimens to induce or maintain remissions in certain sub-populations of patients. Given the efficacy of methotrexate (for early systemic WG) and cotrimoxazole (in WG limited solely to the upper airways) to induce remissions, and the relatively decreased associated morbidity compared with cyclophosphamide, these alternative regimens are preferred in appropriate patients. Similarly, therapeutic options to maintain disease remission that are less toxic than cyclophosphamide should be offered following induction of remission unless a specific contraindication exists. By following this premise, the development of cyclophosphamide-induced morbidities (e.g. haemorrhagic cystitis, uroepithelial cancers and prolonged myelosuppression) may be minimised. Recent investigation has focussed on other immunomodulatory agents (tumour necrosis factor-alpha inhibitors [infliximab and etanercept] and anti-CD20 antibodies [rituximab]) for treating patients with WG. However, the current data are conflicting and difficult to interpret. As a result, these newer agents cannot be recommended for routine use until vigorous clinical study confirms their efficacy.

Anti-Inflammatory Agents↗

PubMed2005

Modified reperfusion in clinical lung transplantation: the results of 100 consecutive cases.

OBJECTIVE: Severe primary graft dysfunction occurs in 10% to 20% of lung transplant recipients and is the leading cause of early death after lung transplantation. We hypothesized that altering the content of the initial reperfusate and maintaining a low reperfusion pressure after surgical implantation would lead to a low incidence of primary graft dysfunction. METHODS: We analyzed the records of all patients who underwent lung transplantation at our institution from March 1, 2000, to August 30, 2004. The modified reperfusion technique involved the insertion of a catheter into the main or individual pulmonary artery after implantation. The recipient blood was depleted of leukocytes; supplemented with nitroglycerin; adjusted for pH and calcium level; enriched with aspartate, glutamate, and dextrose; and then administered into the pulmonary arteries of the newly transplanted lung(s) for the first 10 minutes of reperfusion. Severe primary graft dysfunction was defined as a PaO2/inspired oxygen fraction of less than 150 with diffuse infiltrate on the radiograph in absence of other causes. RESULTS: During this interval, 100 patients underwent lung transplantation with the modified reperfusion technique. Forty-two patients underwent single-lung transplantation, of which 5 patients required cardiopulmonary bypass for the procedure. Fifty-eight patients underwent double-lung transplantation; all double-lung transplantation procedures were performed with patients on cardiopulmonary bypass. There were no technical complications associated with the modified reperfusion. The mean PaO2/inspired oxygen fraction at 6 hours in this cohort was 252 +/- 123 mm Hg. The median number of days on the ventilator was 2. More importantly, the incidence of severe primary graft dysfunction in this cohort was 2.0%. The early survival (30-day or in-hospital mortality) of this group of patients was 97%. CONCLUSIONS: The technique of modified reperfusion in human lung transplantation is associated with a low incidence of severe primary graft dysfunction and favorable short-term outcomes.

Humans↗

PubMed2005

CXCR2/CXCR2 ligand biology during lung transplant ischemia-reperfusion injury.

Lung transplantation is a therapeutic option for a number of end-stage pulmonary disorders. Early lung allograft dysfunction (ischemia-reperfusion injury) continues to be the most common cause of early mortality after lung transplantation and a significant risk factor for the development of bronchiolitis obliterans syndrome. Ischemia-reperfusion injury is characterized histopathologically by lung edema and a neutrophil predominate leukocyte extravasation. The specific mechanism(s) that recruit leukocytes to the lung during post-lung transplantation ischemia-reperfusion injury have not been fully elucidated. Because the ELR+ CXC chemokines are potent neutrophil chemoattractants, we investigated their role during post-lung transplantation ischemic-reperfusion injury. We found elevated levels of multiple ELR+ CXC chemokines in human bronchoalveolar lavage fluid from patients with ischemia-reperfusion injury. Proof of concept studies using a rat orthotopic lung transplantation model of "cold" ischemic-reperfusion injury demonstrated an increase in lung graft neutrophil sequestration and injury. In addition, lung expression of CXCL1, CXCL2/3, and their shared receptor CXCR2 paralleled lung neutrophil infiltration and injury. Importantly, inhibition of CXCR2/CXCR2 ligand interactions in vivo led to a marked reduction in lung neutrophil sequestration and graft injury. Taken together these experiments support the notion that increased expression of ELR+ CXC chemokines and their interaction with CXCR2 plays an important role in the pathogenesis of post-lung transplantation cold ischemia-reperfusion injury.

Animals↗

PubMed2005

Escalation of antimicrobial resistance among Streptococcus pneumoniae: implications for therapy.

Over the past 2 decades, antimicrobial resistance among Streptococcus pneumoniae, the most common cause of community-acquired pneumonia (CAP), has escalated dramatically worldwide. In the late 1970s, strains of pneumococci displaying resistance to penicillin were described in South Africa and Spain. By the early 1990s, penicillin-resistant clones of S. pneumoniae spread rapidly across Europe and globally. Additionally, resistance to macrolides and other antibiotic classes escalated in tandem with penicillin resistance. Six international clones (serotypes 6A, 6B, 9V, 14, 19F, 23F) were responsible for most of these resistant isolates. Currently, 20 to 30% of S. pneumoniae worldwide are multidrug resistant (MDR) (i.e., resistant to > or = 3 different classes of antibiotics). Despite the dramatic escalation in the rate of antimicrobial resistance among pneumococci worldwide, the clinical impact of antimicrobial resistance is difficult to define. Treatment failures due to antibiotic-resistant pneumococci have been reported with meningitis, otitis media, and lower respiratory tract infections, but the relation between drug resistance and treatment failures has not been convincingly established. Clinical failures often reflect factors independent of antimicrobial susceptibility of the infecting organisms. Host factors (e.g., extremes of age; underlying immunosuppressive or debilitating disease; comorbidities), or factors that affect intrinsic virulence of the organisms (e.g., capsular subtype) strongly influence prognosis. Mortality rates are higher in the presence of multilobar involvement, renal insufficiency, need for intensive care unit (ICU) care, hypoxemia, severe derangement in physiological parameters, and comorbidities. Given these confounding factors, determining the impact of antimicrobial resistance on clinical outcomes is difficult, if not impossible. Prospective, randomized trials designed to assess the clinical significance of antimicrobial resistance among pneumococci are lacking, and for logistical reasons, will never be done. Does in vitro resistance translate into clinical failures? Should changing resistance patterns modify our choice of therapy for CAP or for suspected pneumococcal pneumonia? This review discusses several facets, including mechanisms of antimicrobial resistance among specific antibiotic classes, epidemiology and spread of antimicrobial resistance determinants regionally and worldwide, risk factors for acquisition and dissemination of resistance, the impact of key international clones displaying MDR, the clinical impact of antimicrobial resistance, and strategies to limit or curtail antimicrobial resistance among this key respiratory tract pathogen.

Anti-Bacterial Agents↗

PubMed2005

Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome.

Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR(+) CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR(+) CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR(+) CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2(-/-) mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment.

Animals↗

PubMed2005

Pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease limited to the lungs and associated with the histologic appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy. The estimated prevalence in the United States is between 35,000 and 55,000 cases,and evidence suggests that the prevalence is increasing for IPF. Risk factors associated with pulmonary fibrosis include smoking, environmental exposures, gastroesophageal reflux dis-ease, commonly prescribed drugs, diabetes mellitus, infectious agents, and genetic factors. The diagnosis requires a careful history and physical examination, characteristic physiological and radiological studies, and, in some cases, a surgical lung biopsy. The natural history of IPF is not known, but evidence supports the concept of a continuum of idiopathic interstitial pneumonias that may overlap in time. Most patients with IPF succumb to respiratory failure, cardiovascular disease, lung cancer, pulmonary embolism, infection, and other health problems. The median survival time for patients with IPF is less than 3 yr. Factors that predict poor outcome include older age, male gender, severe dyspnea, history of cigarette smoking, severe loss of lung function, appearance and severity of fibrosis on radiological studies, lack of response to therapy,and prominent fibroblastic foci on histopathologic evaluation. Conventional therapy (corticosteroids, azathioprine, cyclophosphamide) provides only marginal benefit. Lung transplantation should be considered for patients with IPF refractory to medical therapy. In light of the poor prognosis and lack of response to available anti-inflammatory therapy, alternative approaches to therapy are being pursued. Emerging strategies to treat patients with IPF include agents that inhibit epithelial injury or enhance repair, anti-cytokine approaches, agents that inhibit fibroblast proliferation or induce fibroblast apoptosis, and other novel approaches.

Adult↗

PubMed2005

Emerging drugs for idiopathic pulmonary fibrosis.

Pulmonary fibrosis is often the end stage of chronic, persistent, low-level lung injury, either of known or unknown cause. The most severe form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF), a disease process of unknown aetiology and one that often leads to respiratory failure and death. At present there are no proven or effective drug therapies for IPF. Recent advances in understanding of disease pathogenesis have focused attention on drug targeting of fibrogenic pathways, as opposed to traditional anti-inflammatory approaches. In this report, the present status of drug development of a number of emerging antifibrotic strategies and agents that may prove more effective in the therapy of this progressive, debilitating and fatal disease are reviewed.

Animals↗

PubMed2004

Increased bronchoalveolar lavage human beta-defensin type 2 in bronchiolitis obliterans syndrome after lung transplantation.

Human beta-defensin-2 (HBD)2 is an antimicrobial peptide that participates in the innate host immune defense. HBD2 is present in bronchoalveolar lavage (BAL) fluid during conditions associated with airway inflammation but not in normal subjects. We measured HBD2 concentrations by semiquantitative Western analysis in BAL of prelung transplant patients (PRE) and postlung-transplant BAL associated with either "quiescent" histopathology (i.e., without acute cellular rejection or infection) (NORMAL POST) or with bronchiolitis obliterans syndrome (BOS). HBD2 levels were not different for PRE (n=9) versus NORMAL POST-transplant BAL specimens (n=22) (204+/-180 vs. 82+/-60 pg/mL; P=NS). The BAL HBD2 concentrations were significantly elevated, however, with BOS (n=8) (1,270+/-430 pg/mL; P<0.001). HBD2 has been previously shown to elicit an adaptive immune response by means of recruitment of immature CD34 dendritic cells and memory (CD4/CD45RO) T lymphocytes through interactions with their chemokine receptor, CCR6. Furthermore, HBD2 with CD14 in human tracheobronchial epithelium can complex with "toll-like receptors" to activate the nuclear factor (NF)-kappaB pathway and therefore promote cytokine gene expression. We therefore speculate that complex interactions between adaptive and innate immunity may contribute to the propagation of airway inflammation in BOS.

Bronchiolitis Obliterans↗

PubMed2004

Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis?

Current guidelines recommend that the clinician, radiologist, and pathologist work together to establish a diagnosis of idiopathic interstitial pneumonia. Three clinicians, two radiologists, and two pathologists reviewed 58 consecutive cases of suspected idiopathic interstitial pneumonia. Each participant was provided information in a sequential manner and was asked to record their diagnostic impression and level of confidence at each step. Interobserver agreement improved from the beginning to the end of the review. After the presentation of histopathologic information, radiologists changed their diagnostic impression more often than did clinicians. In general, as more information was provided the confidence level for a given diagnosis improved, and the diagnoses rendered with a high level of confidence were more likely congruent with the final pathologic consensus diagnosis. The final consensus pathologist diagnosis was idiopathic pulmonary fibrosis in 30 cases. Clinicians identified 75% and radiologists identified 48% of these cases before presentation of the histopathologic information. Histopathologic information has the greatest impact on the final diagnosis, especially when the initial clinical/radiographic diagnosis is not idiopathic pulmonary fibrosis. We conclude that dynamic interactions between clinicians, radiologists, and pathologists improve interobserver agreement and diagnostic confidence.

Diagnosis, Differential↗

PubMed2004

Wegener's granulomatosis: evolving concepts in treatment.

Wegener's granulomatosis (WG), the most common of the pulmonary granulomatous vasculitides, typically involves the upper respiratory tract, lower respiratory tract (bronchi and lung), and kidney, with varying degrees of disseminated vasculitis. Major histological features include a necrotizing vasculitis involving small vessels, extensive "geographic" necrosis, and granulomatous inflammation. Clinical manifestations of WG are protean; virtually any organ can be involved. Further, the spectrum and severity of the disease is heterogeneous, ranging from indolent disease involving only one site to fulminant, multiorgan vasculitis leading to death. The pathogenesis of WG has not been elucidated, but both cellular and humoral components are involved. Circulating antineutrophil cytoplasmic antibodies (cANCA) likely play a role in the pathogenesis and often correlate with activity of the disease. Treatment strategies are evolving. Cyclophosphamide (CYC) plus corticosteroids (CS) is the mainstay of therapy for generalized, multisystemic WG. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3-6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (e.g., methotrexate, azathioprine) is recommended. Further, recent studies suggest that methotrexate combined with CS may be adequate for limited, non-life threatening WG. The role of other immunomodulatory agents (including trimethoprim-sulfamethoxazole) is also explored.

Journal Article↗

PubMed2004

Mechanisms of pulmonary fibrosis.

Tissue injury evokes highly conserved, tightly regulated inflammatory responses and less well-understood host repair responses. Both inflammation and repair involve the recruitment, activation, apoptosis, and eventual clearance of key effector cells. In this review, we propose the concept of pulmonary fibrosis as a dysregulated repair process that is perpetually "turned on" even though classical inflammatory pathways may be dampened or "switched off." Significant regional heterogeneity, with varied histopathological patterns of inflammation and fibrosis, has been observed in individual patients with idiopathic pulmonary fibrosis. We discuss environmental factors and host response factors, such as genetic susceptibility and age, that may influence these varied manifestations. Better understanding of the mechanisms of lung repair, which include alveolar reepithelialization, myofibroblast differentiation/activation, and apoptosis, should offer more effective therapeutic options for progressive pulmonary fibrosis.

Humans↗

PubMed2004

Idiopathic pulmonary fibrosis: emerging concepts on pharmacotherapy.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing disease of the distal air spaces of the lung of unknown aetiology. IPF is usually fatal with a median survival of < 3 years. There are currently no effective pharmacotherapeutic agents for the treatment of IPF. In this review, unifying concepts on the pathogenesis of IPF based on understanding of host responses to tissue injury are presented. These host responses involve tightly regulated and contextually orchestrated inflammatory and repair processes. Dysregulation of either of these processes can lead to pathological outcomes. Fibrosis results from an exaggerated or dysregulated repair process that proceeds 'uncontrolled' even after inflammatory responses have subsided. Disease heterogeneity may arise when inflammation and repair are in different (dys)regulatory phases, thus accounting for regional disparity. Usual interstitial pneumonia (UIP), the histopathological correlate of clinical IPF, represents a more fibrotic tissue reaction pattern and for which anti-inflammatory agents are ineffective. Emerging 'antifibrotic' drugs and strategies for UIP/IPF are discussed. The importance of accurately phenotyping a highly heterogeneous disease process that may require individualised and 'combined' therapies is emphasised.

Acetylcysteine↗